Process for the synthesis of triazoles

ABSTRACT

The present invention relates to processes for the preparation of triazoles. These compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.

FIELD OF THE INVENTION

The present invention relates to processes for synthesizinganti-infective, anti-proliferative, anti-inflammatory, and prokineticagents. More particularly, the invention relates to processes forsynthesizing triazoles that are useful as such therapeutic agents.

BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the1940s, many new compounds have been discovered or specifically designedfor use as antibiotic agents. It was once believed that infectiousdiseases could be completely controlled or eradicated with the use ofsuch therapeutic agents. However, such beliefs have been shaken by thefact that strains of cells or microorganisms resistant to currentlyeffective therapeutic agents continue to evolve. In fact, virtuallyevery antibiotic agent developed for clinical use has ultimatelyencountered problems with the emergence of resistant bacteria. Forexample, resistant strains of Gram-positive bacteria such asmethicillin-resistant staphylocci, penicillin-resistant streptococci,and vancomycin-resistant enterococci have developed, which can causeserious and even fatal results for patients infected with such resistantbacteria. Bacteria that are resistant to macrolide antibiotics, i.e.,antibiotics based on a 14- to 16-membered lactone ring, have developed.Also, resistant strains of Gram-negative bacteria such as H. influenzaeand M. catarrhalis have been identified. See, e.g., F. D. Lowry,“Antimicrobial Resistance: The Example of Staphylococcus aureus,” J.Clin. Invest, vol. 111, no. 9, pp. 1265-1273 (2003); and Gold, H. S. andMoellering, R. C., Jr., “Antimicrobial-Drug Resistance,” N. Engl. J.Med., vol. 335, pp. 1445-53 (1996).

The problem of resistance is not limited to the area of anti-infectiveagents, because resistance has also been encountered withanti-proliferative agents used in cancer chemotherapy. Therefore, thereexists a need for new anti-infective and anti-proliferative agents thatare both effective against resistant bacteria and resistant strains ofcancer cells.

In the antibiotic area, despite the problem of increasing antibioticresistance, no new major classes of antibiotics have been developed forclinical use since the approval in the United States in 2000 of theoxazolidinone ring-containing antibiotic,N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methylacetamide, which is known as linezolid and is sold under the trade nameZYVOX®. See, R. C. Moellering, Jr., “Linezolid: The First OxazolidinoneAntimicrobial,” Annals of Internal Medicine, vol. 138, no. 2, pp.135-142 (2003).

Linezolid was approved for use as an anti-bacterial agent active againstGram-positive organisms. Unfortunately, linezolid-resistant strains oforganisms are already being reported. See, Tsiodras et al, Lancet, vol.358, p. 207 (2001); Gonzales et al, Lancet, vol. 357, p. 1179 (2001);Zurenko et al., Proceedings Of The 39^(th) Annual InterscienceConference On Antibacterial Agents And Chemotherapy (ICAAC), SanFrancisco, Calif., USA (September 26-29, 1999). Because linezolid isboth a clinically effective and commercially significant anti-microbialagent, investigators have been working to develop other effectivelinezolid derivatives.

Notwithstanding the foregoing, there is an ongoing need for newanti-infective and anti-proliferative agents. Furthermore, because manyanti-infective and anti-proliferative agents have utility asanti-inflammatory agents and prokinetic agents, there is also an ongoingneed for new compounds useful as anti-inflammatory and prokineticagents. Because of these needs for these therapeutic agents there is acorresponding need for processes for making these compounds and keyintermediates in the synthesis thereof.

SUMMARY OF THE INVENTION

The present invention relates to processes for preparing triazolecompounds, particularly 1,2,3-triazole compounds, i.e. compounds inwhich the three nitrogens of the triazole ring are in the adjacent “1”,“2”, and “3” positions.

The processes of the invention can tolerate a wide variety of functionalgroups, so various substituted starting materials can be used. Theprocesses generally provide the desired final triazole compound at ornear the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester, or prodrug thereof.

The foregoing and other aspects and embodiments of the invention can bemore fully understood by reference to tire following detaileddescription and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to processes for preparing triazolecompounds, particularly 1,2,3-triazole compounds, i.e. compounds inwhich the three nitrogens of the triazole ring are in the adjacent “1”,“2”, and “3” positions. The present invention also relates to theintermediate compounds for preparing these triazole compounds.

The triazoles are connected to the remainder of the molecule, typicallyat the “4” position, i.e. at one of the remaining carbon atoms of thetriazole ring. It should be noted that this numbering convention is usedfor convenience, and that the exact numbering will depend on thenumbering convention used, and is not intended as a limitation. Theimportant aspects of the triazoles of the present invention are that (a)the nitrogen atoms of the triazole ring are in an adjacent or “1”, “2”,and “3” orientation and (b) the triazole is attached to the remainder ofthe molecule via one of the remaining two carbon atoms of the triazolering.

The following examples further illustrate this point and also provide anexample of a numbering system for the triazole ring.

An exemplary numbering scheme for triazole, Compound A, is a follows:

An nonlimiting example of a triazole compound, Compound B (also compound1 of Table 1), of the present invention, showing a numbering conventionin which the triazole ring is attached at the “4” position to theremainder of the compound, and where the remaining carbon atom atposition “5” of the triazole ring is unsubstituted, i.e. where it has ahydrogen, is as follows:

It should be recognized that the triazole ring is a 5-memberedheteroaromatic ring and that the location of the two double bonds drawnin most representations is an arbitrary depiction of one of the multiplestructures that can be drawn, and is used for convenience and notintended as a limitation. In fact, five different structures, sometimescalled tautomeric structures, can be drawn to depict a 1,2,3-triazole.These tautomeric structures can be indicated with double-headed arrowsbetween each structure, indicating that the molecules so represented arein equilibrium with each other. As a nonlimiting example, the followingstructures can be used to depict the compounds 1,2,3-triazole.

For example, for Compound B, the following tautomeric structures can bedrawn:

The triazole compounds of the present invention are useful aspharmaceutical agents, particularly as anti-infective agents and/or asanti-proliferative agents, for treating humans and animals, particularlyfor treating humans and other mammals. The compounds may be used withoutlimitation, for example, as anti-cancer, anti-microbial, anti-bacterial,anti-fungal, anti-parasitic and/or anti-viral agents. Further, thepresent invention provides a family of compounds that can be usedwithout limitation as anti-inflammatory agents, for example, for use intreating chronic inflammatory airway diseases, and/or as prokineticagents, for example, for use in treating gastrointestinal motilitydisorders such as gastroesophageal reflux disease, gastroparesis(diabetic and post surgical), irritable bowel syndrome, andconstipation. Further, the compounds can be used to treat or prevent adisease state in a mammal caused or mediated by a nonsense or missensemutation.

Following synthesis, a therapeutically effective amount of one or moreof the compounds can be formulated with a pharmaceutically acceptablecarrier for administration to a human or an animal. Accordingly, thecompounds or the formulations can be administered, for example, viaoral, parenteral, or topical routes, to provide an effective amount ofthe compound. In alternative embodiments, the compounds prepared inaccordance with the present invention can be used to coat or impregnatea medical device, e.g., a stent.

Compounds synthesized according to the methods of the invention may beused to treat a disorder in a mammal, particularly humans, byadministering to the mammal an effective amount of one or more compoundsof the invention thereby to ameliorate a symptom of a particulardisorder. Such a disorder can be selected from a skin infection,nosocomial pneumonia, post-viral pneumonia, an abdominal infection, aurinary tract infection, bacteremia, septicemia, endocarditis, anatrio-ventricular shunt infection, a vascular access infection,meningitis, surgical prophylaxis, a peritoneal infection, a boneinfection, a joint infection, a methicillin-resistant Staphylococcusaureus infection, a vancomycin-resistant Enterococci infection, alinezolid-resistant organism infection, and tuberculosis.

1. Definitions

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Ringdouble bonds, as used herein, are double bonds that are formed betweentwo adjacent ring atoms (e.g., C═C, C═N, or N═N).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The compounds described herein may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic, and geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomeric form is specifically indicated. Alltautomers of shown or described compounds are also considered to be partof the present invention.

When any variable (e.g., R¹) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹ moieties,then the group may optionally be substituted with up to two R¹ moietiesand R¹ at each occurrence is selected independently from the definitionof R¹. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

When an atom or chemical moiety is followed by a subscripted numericrange (e.g., C₁₋₆), the invention is meant to encompass each numberwithin the range as well as all intermediate ranges. For example, “C₁₋₆alkyl” is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5,1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6carbons.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.

As used herein, “alkenyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon double bonds occurring at any stable point along thechain. For example, C₂₋₆ alkenyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkenyl groups. Examples of alkenyl include, but are not limitedto, ethenyl and propenyl.

As used herein, “alkynyl” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or morecarbon-carbon triple bonds occurring at any stable point along thechain. For example, C₂₋₆ alkynyl is intended to include C₂, C₃, C₄, C₅,and C₆ alkynyl groups. Examples of alkynyl include, but are not limitedto, ethynyl and propynyl.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo.

“Counterion” is used to represent a small, negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic ring” is intended to meanany stable monocyclic, bicyclic, or tricyclic ring having the specifiednumber of carbons, any of which may be saturated, unsaturated, oraromatic. For example a C₃₋₁₄ carbocycle is intended to mean a mono-,bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14carbon atoms. Examples of carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are alsoincluded in the definition of carbocycle, including, for example,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbonatoms link two non-adjacent carbon atoms. Preferred bridges are one ortwo carbon atoms. It is noted that a bridge always converts a monocyclicring into a tricyclic ring. When a ring is bridged, the substituentsrecited for the ring may also be present on the bridge. Fused (e.g.,naphthyl and tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean any stable monocyclic, bicyclic, or tricyclic ring which issaturated, unsaturated, or aromatic and comprises carbon atoms and oneor more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur. Abicyclic or tricyclic heterocycle may have one or more heteroatomslocated in one ring, or the heteroatoms may be located in more than onering. The nitrogen and sulfur heteroatoms may optionally be oxidized(i.e., N→O and S(O)_(p), where p=1 or 2). When a nitrogen atom isincluded in the ring it is either N or NH, depending on whether or notit is attached to a double bond in the ring (i.e., a hydrogen is presentif needed to maintain the tri-valency of the nitrogen atom). Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, as defined). The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. A nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. Bridged rings are also included in the definition ofheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Bridgesinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge. Spiro and fused rings are also included.

As used herein, the term “aromatic heterocycle” or “heteroaryl” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclicaromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclicaromatic heterocyclic ring which consists of carbon atoms and one ormore heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6heteroatoms, independently selected from nitrogen, oxygen, and sulfur.In the case of bicyclic heterocyclic aromatic rings, only one of the tworings needs to be aromatic (e.g., 2,3-dihydroindole), though both may be(e.g., quinoline). The second ring can also be fused or bridged asdefined above for heterocycles. The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, asdefined). The nitrogen and sulfur heteroatoms may optionally be oxidized(i.e., N→O and S(O)_(p), where p=1 or 2). It is to be noted that totalnumber of S and O atoms in the aromatic heterocycle is riot more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As used herein, the term “amine protecting group” is intended to mean afunctional group that converts an amine, amide, or othernitrogen-containing moiety into a different chemical group that issubstantially inert to the conditions of a particular chemical reaction.Amine protecting groups are preferably removed easily and selectively ingood yield under conditions that do not affect other functional groupsof the molecule. Examples of amine protecting groups include, but arenot limited to, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,t-butyloxycarbonyl, p-methoxybenzyl, methoxymethyl, tosyl,trifluoroacetyl, trimethylsilyl, fluorenyl-methyloxycarbonyl,2-trimethylsilyl-ethyoxycarbonyl,1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, andbenzyloxycarbonyl. Other suitable amine protecting groups arestraightforwardly identified by those of skill in the art, e.g., byreference to Green & Wuts, Protective Groups in Organic Synthesis, 3dEd. (1999, John Wiley & Sons, Inc.).

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines, alkali or organic salts ofacidic residues such as carboxylic acids, and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, 2,3,4,5-tetrahydroxyhexane-1,6-dicarboxylic,2,5-dihydroxybenzoic, acetic, adipic, ascorbic, benzene sulfonic,benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, hyppuric,isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic,malonic, mandelic, methane sulfonic, napsylic, naphthalenedisulfonic,nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic,sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic(e.g. p-toluene sulfonic) acid.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). Forexample, salts can include, but are not limited to, the hydrochlorideand acetate salts of the aliphatic amine-containing, hydroxylamine-containing, and imine-containing compounds of the presentinvention.

Additionally, the compounds of the present invention, and particularlythe salts of the compounds, can exist in either hydrated or unhydrated(the anhydrous) form or as solvates with other solvent molecules.Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.Nonlimiting examples of solvates include ethanol solvates, acetonesolvates, etc.

Pharmaceutically acceptable ester means an esterified carboxylic acidmoiety (i.e. esterified or reacted with a pharmaceutically acceptablealcohol) or esterified hydroxyl moiety (i.e. esterified or reacted witha pharmaceutically acceptable carboxylic acid) of the compounds andintermediates of the present invention.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention can be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of the presentinvention.

All pharmaceutically acceptable salts, esters, and prodrugs of thecompounds of the present invention, and of their intermediates arecontemplated as within the scope of the present invention.

All percentages and ratios used herein, unless otherwise indicated, areby weight.

Throughout the description, where compositions are described as having,including, or comprising specific components, it is contemplated thatcompositions also consist essentially of, or consist of, the recitedcomponents. Similarly, where processes are described as having,including, or comprising specific process steps, the processes alsoconsist essentially of, or consist of, the recited processing steps.Further, the process steps are numbered for convenience in a claim orgroup of dependent claims. Moreover, two or more steps or actions may beconducted simultaneously. Additionally, single steps, or less than allthe steps, or various permutations of the steps of the present inventioncan also be conducted and are contemplated within the present invention.It should be recognized that the steps and compound numbers as labeledin the processes of the present invention are provided for convenienceand not intended to limit the scope of the invention.

2. Processes of the Invention

The processes of the present invention involve a cycloaddition reactionof an azide and an alkyne to form a triazole moiety (e.g., step 1).Generally, the cycloaddition reaction is conducted at an elevatedtemperature, i.e. with the addition of heat, because when the reactionis run at normal room temperature or at a slightly elevated temperature,i.e. slightly above normal room temperature, the reaction tends not togo to completion, or sometimes not at all.

Alternatively, the cycloaddition reaction (e.g., step 1) can be run inthe presence of a copper catalyst, in such instances the addition ofheat not being necessary. The copper catalyst is preferably a copper (I)catalyst, examples of preferred copper catalysts being CuCl, CuBr, CuI,CuNO₃, and Cu₂SO₄, with CuI being most preferred. However, the coppercatalyzed reaction has some potential safety concerns because of thedanger of having an azide in the presence of copper, which canpotentially trigger an explosive decomposition of the azide. Therefore,it is preferred that the cycloaddition reaction to form the triazole becarried out without a copper catalyst. When the reaction is carried outwithout a catalyst, the reaction has the advantage that it can befacilitated by heating, i.e. run under thermal conditions.

Because the triazole moiety can be relatively reactive, it is preferableto protect or mask the triazole so that further chemical transformationscan be carried out on other parts of the molecule. In other words, eventhough an unsubstituted organic triazole can be made by thecycloaddition of an inorganic azide, e.g. sodium azide, and an alkyne,it is preferable to make a masked or protected azide, which issubsequently unmasked or deprotected.

Therefore, the processes of the present invention involve the synthesisof a masked triazole, i.e. a protected triazole, which is furtherreacted on another part of the molecule to make a biaryl moiety.Specifically, in tire processes of the present invention, the biarylmoiety is preferably made by a Suzuki type coupling reaction (e.g., step3). The biaryl adduct made from the Suzuki type coupling can then eitherbe deprotected to release or unmask the triazole, or it can first besubjected to further chemical transformations.

Generally the invention relates to a process for preparing a compoundhaving the formula:

wherein the process includes the steps of:

-   (Step 1) combining a compound (II) having the formula:

with a compound (HI) having the formula:

X—N₃   Compound (III)

in a solvent, optionally in the presence of a copper catalyst, to form acompound (IV) having the formula:

(Step 2) combining a compound (IV) with a compound (V) having theformula:

in a solvent in the presence of a reducing agent to form a compound (VI)having the formula:

(Step 3) combining compound (VI) with a compound (VII) having theformula:

in a solvent in the presence of a base and a palladium catalyst to forma compound (VIII) having the formula:

and (Step 4) heating a compound (VIII), in a solvent in the presence ofan acid, followed by the addition of a neutralizing agent to form acompound (I);wherein:

-   -   A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, and        pyridazinyl;    -   B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, and        pyridazinyl;    -   Het-CH₂—R³ is selected from

-   -   Q is a borane having the formula —BY₂, wherein        -   Y, at each occurrence, independently is selected from:            -   a) —OH, b) —OC₁₋₆ alkyl, c) —OC₂₋₆ alkenyl, d) —OC₂₋₆                alkynyl,            -   e) —OC₁₋₁₄ saturated, unsaturated, or aromatic                carbocycle, f) C₁₋₆ alkyl, g) C₂₋₆ alkenyl, h) C₂₋₆                alkynyl, and i) C₁₋₁₄ saturated, unsaturated, or                aromatic carbocycle,                -   wherein any of b)-i) optionally is substituted with                    one or more halogens;        -   alternatively, two Y groups taken together comprise a            chemical moiety selected from: a) —OC(R⁴)(R⁴)C(R⁴)(R⁴)O—,            and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—;    -   alternatively, Q is a BF₃ alkali metal salt, a BF₃ ammonium        salt, a BF₃ tetralkyl ammonium salt, a BF₃ phosphate salt, or        9-borabicyclo[3.3.1]nonane;    -   X is selected from:    -   a) —CH₂-phenyl, b) —SO-phenyl, c) —SO₂-phenyl, d)        —CH₂O-phenyl, e) —CH₂O—CH₂-phenyl, f) —CH₂—O—R₂₁, g) —Si—(R²¹)₃,        and h) —P(O)—(W)₂,        -   wherein each W is independently C₁₋₆ alkyl or phenyl; each            R²¹ is independently C₁₋₆ alkyl; each phenyl in a), b), c),            d), e), or h) is optionally substituted with one or more            R¹², wherein R¹² is selected from:        -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR²², g) —CN, h)            —NO₂, i) —NR²²R²², j) —C(O)R²², k) —C(O)OR²², l)            —OC(O)R²², m) —C(O)NR²²R²², n) —NR²²C(O)R²², o)            —OC(O)NR²²R²², p) —NR²²C(O)OR²², q) —NR²²C(O)NR²²R²², r)            —C(S)R²², s) —C(S)OR²², t) —OC(S)R²², u) —C(S)NR²²R²², v)            —NR²²C(S)R²², w) —OC(S)NR²²R²², x) —NR²²C(S)OR²², y)            —NR²²C(S)NR²²R²², z) —C(NR²²)R²², aa) —C(NR²²)OR²², bb)            —OC(NR²²)R²², cc) —C(NR²²)NR²²R²², dd) —NR²²C(NR²²)R²², ee)            —OC(NR²²)NR²²R²², ff) —NR²²C(NR²²)OR²², gg)            —NR²²C(NR²²)NR²²R²², hh) —S(O)_(p)R²², ii) —SO₂NR²²R²² and            jj) R²², wherein each R²² is independently, H or C₁₋₆ alkyl;    -   Z is selected from: a) I, b) Br, c) Cl, d) R⁹OSO₃—, and e)        N₂BF₄;    -   R¹, at each occurrence, independently is selected from:        -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h)            —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m)            —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p)            —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t)            —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x)            —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴,            bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee)            —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴, hh)            —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴;    -   R², at each occurrence, independently is selected from:        -   a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h)            —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m)            —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p)            —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t)            —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x)            —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴,            bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee)            —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴, hh)            —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴;    -   R³ is selected from:        -   a) —OR⁴, b) —NR⁴R⁴, c) —C(O)R⁴, d) —C(O)OR⁴, e) —OC(O)R⁴, f)            —C(O)NR⁴R⁴, g) —NR⁴C(O)R⁴, h) —OC(O)NR⁴R⁴, i)            —NR⁴C(O)OR⁴, j) —NR⁴C(O)NR⁴R⁴, k) —C(S)R⁴, l) —C(S)OR⁴, m)            —OC(S)R⁴, n) —C(S)NR⁴R⁴, o) —NR⁴C(S)R⁴, p) —OC(S)NR⁴R⁴, q)            —NR⁴C(S)OR⁴, r) —NR⁴C(S)NR⁴R⁴, s) —C(NR⁴)R⁴, t)            —C(NR⁴)OR⁴, u) —OC(NR⁴)R⁴, v) —C(NR⁴)NR⁴R⁴, w)            —NR⁴C(NR⁴)R⁴, x) —OC(NR⁴)NR⁴R⁴, y) —NR⁴C(NR⁴)OR⁴, z)            —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, and cc) R⁴;    -   R⁴, at each occurrence, independently is selected from:        -   a) H, b) —OR⁶, c) C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆            alkynyl, f) C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle, g) 3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, h) —C(O)—C₁₋₆            alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k)            —C(O)—[C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle], l) —C(O)—[3-14 membered saturated, unsaturated,            or aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur], m) —C(O)O—C₁₋₆            alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p)            —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle,            and q) —C(O)O-3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur,            -   wherein any of c)-q) optionally is substituted with one                or more R⁵ groups;    -   R⁵, at each occurrence, is independently selected from:        -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁶, h)            ═NOR⁶, i) ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l) —CN, m) —NO₂, n)            —NR⁶R⁶, o) —C(O)R⁶, p) —C(O)OR⁶, q) —OC(O)R⁶, r)            —C(O)NR⁶R⁶, s) —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u)            —NR⁶C(O)OR⁶, v) —NR⁶C(O)NR⁶R⁶, w) —C(S)R⁶, x) —C(S)OR⁶, y)            —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa) —NR⁶C(S)R⁶, bb)            —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶, ee)            —C(NR⁶)R⁶, ff) —C(NR⁶)OR⁶, gg) —OC(NR⁶)R⁶, hh)            —C(NR⁶)NR⁶R⁶, ii) —NR⁶C(NR⁶)R⁶, jj) —OC(NR⁶)NR⁶R⁶, kk)            —NR⁶C(NR⁶)OR⁶, ll) —NR⁶C(NR⁶)NR⁶R⁶, mm) —S(O)_(p)R⁶, nn)            —SO₂NR⁶R⁶, oo) —N₃, pp) —Si(CH₃)₃, qq) —O—Si(CH₃)₃, rr)            —Si(C₂H₅)₂CH₃, ss) —O—Si(C₂H₅)₂CH₃, and tt) R₆;    -   R⁶, at each occurrence, independently is selected from:        -   a) H, b) —OR⁸, c) C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆            alkynyl, f) C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle, g) 3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, h) —C(O)—C₁₋₆            alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k)            —C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle, l) —C(O)-3-14 membered saturated, unsaturated,            or aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆            alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p)            —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle,            and q) —C(O)O-3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur,            -   wherein any of c)-q) optionally is substituted with one                or more R⁷ groups;    -   R⁷, at each occurrence, independently is selected from:        -   a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h)            ═NOR⁸, i) ═N—NR⁸R⁸, j) —CF₃, k) —OR⁸, l) —CN, m) —NO₂, n)            —NR⁸R⁸, o) —C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r)            —C(O)NR⁸R⁸, s) —NR⁸C(O)R⁸, t) —OC(O)NR⁸R⁸, u)            —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w) —C(S)R⁸, x) —C(S)OR⁸, y)            —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa) —NR⁸C(S)R⁸, bb)            —OC(S)NR⁸R⁸, cc) —NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸, ee)            —C(NR⁸)R⁸, ff) —C(NR⁸)OR⁸, gg) —OC(NR⁸)R⁸, hh)            —C(NR⁸)NR⁸R⁸, ii) —NR⁸C(NR⁸)R⁸, jj) —OC(NR⁸)NR⁸R⁸, kk)            —NR⁸C(NR⁸)OR⁸, ll) —NR⁸C(NR⁸)NR⁸R⁸, mm) —S(O)_(p)R⁸, nn)            —SO₂NR⁸R⁸, oo) C₁₋₆ alkyl, pp) C₂₋₆ alkenyl, qq) C₂₋₆            alkynyl, rr) C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle, and ss) 3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur,            -   wherein any of oo)-ss) optionally is substituted with                one or more moieties selected from R⁸, F, Cl, Br, I,                —CF₃, —OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸, —C(O)OR⁸,                —OC(O)R⁸, —C(O)NR⁸R⁸, —NR⁸C(O)R⁸, —OC(O)NR⁸R⁸,                —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸, —OC(S)R⁸,                —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸,                —NR⁸C(S)NR⁸R⁸, —C(NR⁸)R⁸, —C(NR⁸)OR⁸, —OC(NR⁸)R⁸,                —C(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)R⁸, —OC(NR⁸)NR⁸R⁸,                —NR⁸C(NR⁸)OR⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸,                and-S(O)_(p)R⁸;    -   R⁸, at each occurrence, independently is selected from:        -   a) H, b) an amine protecting group, c) C₁₋₆ alkyl, d) C₂₋₆            alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated, unsaturated,            or aromatic carbocycle, g) 3-14 membered saturated,            unsaturated, or aromatic heterocycle comprising one or more            heteroatoms selected from nitrogen, oxygen, and sulfur, h)            —C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆            alkynyl, k) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic            carbocycle, l) —C(O)-3-14 membered saturated, unsaturated,            or aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆            alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p)            —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle,            and q) —C(O)O-3-14 membered saturated, unsaturated, or            aromatic heterocycle comprising one or more heteroatoms            selected from nitrogen, oxygen, and sulfur,            -   wherein any of c)-q) optionally is substituted with one                or more moieties selected from F, Cl, Br, I, —CF₃, —OH,                —OC₁₋₆ alkyl, —SH, —SC₁₋₆ alkyl, —CN, —NO₂, —NH₂,                —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)C₁₋₆ alkyl,                —C(O)OC₁₋₆ alkyl, —C(O)NH₂, —C(O)NHC₁₋₆ alkyl,                —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)C₁₋₆ alkyl, —SO₂NH₂—,                —SO₂NHC₁₋₆ alkyl, —SO₂N(C₁₋₆ alkyl)₂, and —S(O)_(p)C₁₋₆                alkyl;    -   R⁹ is selected from: a) C₁₋₆ alkyl, b) phenyl, and c) toluyl,        wherein any of a)-c) optionally is substituted with one or more        moieties selected from F, Cl, Br, and I;    -   R¹⁰ is selected from H and C₁₋₈ alkyl;    -   R¹¹ is selected from H and C₁₋₈ alkyl;    -   m is 0, 1, 2, 3, or 4;    -   n is 0, 1, 2, 3, or 4;    -   p, at each occurrence, independently is 0, 1, or 2;    -   s is 1, 2, 3, 4, 5, or 6; and    -   t is 0, 1, 2, 3, 4, 5, or 6,    -   wherein —(CH₂)_(s)— and —(CH₂)_(t), other than when t is 0, are        optionally substituted on any carbon atom thereof by one or more        moieties selected from a) C₁₋₆ alkyl, b) C₁₋₆ alkenyl, c)        phenyl, d) hydroxyl, e) C₁₋₆ alkoxy, f) F, g) Cl, h) Br, i)        I, j) ═O, and k) benzyl.

As used in compound (I), (VIII), (VIII-b-P), (VIII-b), (I-b), Bindicates the vatiable B, as defined above. However, as used in theborane compound Q, (—BY₂), B indicates the element boron.

The azide compounds (e.g., Compound (III) utilized in step 1) useful inthe present invention are designated as X—N3. A wide array of azidecompounds is useful here. Specifically, X is selected from a)—CH2-phenyl, b) —SO-phenyl, c) —SO2-phenyl, d) —CH2-O-phenyl, e)—CH2-O—CH2-phenyl, f) —CH2-O—R21, g) —Si—(R21)3, and h) —P(O)—(W)2 (seedefinitions of variables above). In further embodiments, X ispara-methoxybenzyl, para-toluenesulfonyl, trimethylsilyl, anddiphenylphosphoryl. In yet further embodiments, X is para-methoxybenzyl.

In some embodiments, the process of the invention further comprises(Step 5): combining compound (I) with an acid to form a salt thereof.

In some embodiments, groups Q and Z can be reversed (e.g., Q is presentin compound VII and Z is present in compound V) for the Suzuki couplingstep of the present invention.

The invention further relates to a process for preparing a compound (I)having the formula

comprising the steps of:

-   (Step 1) combining a compound (II) having the formula:

with a compound (III) having the formula:

X—N3   Compound (III)

in a solvent, optionally in the presence of a copper catalyst, to form acompound (IV) having the formula:

-   (Step 2) combining a compound (IV) with a compound (V-a) having the    formula

in a solvent in the presence of a reducing agent to form a compound(VI-a) having the formula:

-   (Step 3) combining compound (VI-a) with a compound (VII-a) having    the formula:

in a solvent in the presence of a base and a palladium catalyst to forma compound (VIII) having the formula,

(Step 4) heating a compound (VIII), in a solvent in the presence of anacid, followed by the addition of a neutralizing agent to form acompound (I);wherein A, B, Het-CH₂—R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and tare as defined above.

In some embodiments, this process further comprises (Step 5): combiningcompound (I) with an acid to form a salt thereof.

Further, the invention relates to a process for preparing a compound (I)having the formula

comprising the step of (Step 4) heating a compound (VIII) having theformula:

in a solvent in the presence of an acid, followed by the addition of aneutralizing agent to form a compound (I); wherein A, B, Het-CH₂-R³, Q,Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and t are as defined above. Thisprocess can further include (Step 5): combining a compound (I) with anacid to form a salt thereof.

Further, the invention relates to a process for preparing a compound(I-b) having the formula

comprising the steps of:

-   (Step 1) combining a compound (II-b) having the formula:

with a compound (III) having the formula:

X—N₃   Compound (III)

in a solvent, optionally in the presence of a copper catalyst, to form acompound (IV-b) having the formula:

(Step 2) combining a compound (IV-b) with a compound (V) having theformula:

in a solvent in the presence of a reducing agent to form compound (VI-b)having the formula

(Step 2-1) combining a compound (VI-b) with a protecting group reagentin a solvent in the presence of a base to form protected compound(VI-b-P) having the formula

(Step 3) combining a compound (VI-b-P) with a compound (VII) having theformula:

in a solvent in the presence of a base and a palladium catalyst to formcompound (VIII-b-P) having the formula:

(Step 3-1) deprotecting a compound (VIII-b-P) in a solvent to formcompound (VIII-b) or a salt thereof having the formula:

(Step 4) heating compound (VIII-b) in a solvent in the presence of anacid, followed by the addition of a neutralizing agent to form compound(I-b);wherein A, B, Het-CH₂-R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and tare as defined above. In some embodiments, this process furthercomprises (Step 5): combining compound (I-b) with an acid to form a saltthereof.

Further, the invention relates to a process for preparing a compound(I-b) having the formula

comprising the steps of:

-   (Step 1) combining a compound (II-b) having the formula:

with a compound (III) having the formula:

X—N₃   Compound (III)

in a solvent, optionally in the presence of a copper catalyst, to form acompound (IV-b) having the formula:

(Step 2) combining a compound (IV-b) with a compound (V) having theformula:

in a solvent in the presence of a reducing agent to form compound (VI-b)having the formula

(Step 2-1) combining a compound (VI-a) with a protecting group reagentin a solvent in the presence of a base to form protected compound(VI-b-P) having the formula:

(Step 3) combining a compound (VI-b-P) with a compound (VII-a) havingthe formula:

in a solvent in the presence of a base and a palladium catalyst to formcompound (VIII-b-P) having the formula:

(Step 3-1) deprotecting a compound (VIII-b-P) in a solvent in thepresence of an acid to form compound (VIII-b) having the formula:

(Step 4) heating compound (VIII-b) in a solvent in the presence of anacid, followed by the addition of a neutralizing agent to form compound(I-b);wherein A, B, Het-CH₂—R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and tare as defined above. This process can further include (Step 5)combining compound (I-b) with an acid to form a salt thereof.

Further, the invention relates to a process for preparing a compoundhaving the formula: formula:

wherein the process includes the steps of:

-   (Step 1) combining a compound (II) having the formula:

with a compound (III) having the formula:

X—N₃   Compound (III)

in a solvent, optionally in the presence of a copper catalyst, to form acompound (IV), wherein X, R¹¹, and s, are as defined above.

In some embodiments, the step 4 reaction is maintained at a temperatureselected from about 40° C. to about 100° C. In some embodiments, thetemperature of the step 4 reaction is between 60 and 70° C. For example,the reaction can be between 60 and 65° C. (inclusive) or between 65 and70° C. (inclusive).

In some embodiments, the step 4 reaction is maintained at a temperaturebetween 60 and 70° C. (inclusive) for 12 to 20 hours (inclusive) priorto the addition of a neutralizing agent. In some embodiments thereaction can be between 60 and 65° C. (inclusive) for about 20 hours andin some other embodiments the reaction can be between 65 and 70° C.(inclusive) for about 12 hours.

Note that in the foregoing that the substituent “X”, when present, isshown as being on a variable position of the triazole ring, and is meantto represent that in the resulting intermediate triazole formed in Step1 and carried through other steps, two different isomeric compounds canbe produced. The “X” substituent in the intermediate triazole issubsequently removed in Step 4 to generally form a single compound.

Furthermore, because the compounds of the present invention not onlyhave a triazole moiety, but also a biaryl moiety, the processes of thepresent invention involve a Suzuki-type coupling reaction, i.e. Step 3,between an aryl borane compound (e.g., an aryl boronic acid, arylboronic ester, aryl boronic halide, or organoborane) and an arylcompound having an electronegative substituent (e.g., an aryl halide oraryl sulfonate) in a solvent in the presence of a base and a palladiumcatalyst. See, e.g., Miyaura et al., Tetrahedron Letters, 3437 (1979),and Miyaura & Suzuki, Chem. Comm., 866 (1979). See for example PCTapplication No. WO 2005/012271, to Rib-X Pharmaceuticals, Inc.,published Feb. 10, 2005; and Suzuki & Brown, Organic Synthesis ViaBoranes Volume 3: Suzuki Coupling, (Aldrich, 2003).

In some embodiments, R¹¹ is H, i.e. the amine starting material is aprimary amine. In these embodiments, the processes of the presentinvention involve additional optional steps of protecting the resultingsecondary amine that is obtained after step (2) before carrying out theSuzuki type coupling on the compound to form the biaryl system. When theprocesses of the present invention include protecting the secondaryamine, the protecting group is then generally removed, usually after theSuzuki type coupling is completed, and the remaining steps of thereaction can be carried out. Examples of suitable amine protectinggroups include benzyl, t-butyldimethylsilyl, t-butdyldiphenylsilyl,t-butyloxycarbonyl, p-methoxybenzyl, methoxymethyl, tosyl,trifluoroacetyl, trimethylsilyl, fluorenyl-methyloxycarbonyl,2-trimethylsilyl-ethyoxycarbonyl,1-methyl-1-(4-biphenylyl)ethoxycarbonyl, allyloxycarbonyl, andbenzyloxycarbonyl. The addition and subsequent removal of the protectinggroups is generally effected using well-known protecting groupprecursors, reagents, and reaction conditions. See T. W. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) ed., JohnWiley & Sons, New York, N.Y. (1999); and P. J. Kocienski and GeorgThieme, Protecting Groups, Verlag, New York, N.Y. (1994).

In some examples of the compounds of the invention, the Z group can be ahalogen or a sulfonate. Examples of suitable sulfonates include, but arenot limited to, methanesulfonate (“mesylate”), trifluoromethanesulfonate(“triflate”), and p-toluenesulfonate (“tosylate”). In preferredembodiments, the Z group is I. Q groups include, for example, —B(OH)₂,—BF2.KF, and

In any of the above processes, the base can be selected from alkalimetal hydroxides, alkali metal carbonates, alkali metal fluorides,trialkyl amines, and mixtures thereof. Examples of suitable basesinclude potassium carbonate, sodium carbonate, sodium methoxide, sodiumethoxide, potassium fluoride, triethylamine, diisopropylethylamine, andmixtures thereof. In certain embodiments, the ratio of equivalents ofbase to equivalents of compound (I), (IV), (V), (V-a), (VIII), (VII-a),(IX), or (XII) is about 3:1.

The catalyst used in (Step 3) can be a palladium catalyst, for example,a ligand coordinated palladium(0) catalyst (e.g., atetrakis(trialkylphosphine)palladium(0) or atetrakis(triarylphosphine)palladium(0) catalyst) or a ligand coordinatedpalladium(II) catalyst. Suitable catalysts include, for example,tetrakis(triphenylphosphine)palladium(0),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, andpalladium(II) chloride. In particular embodiments, the catalyst istetrakis(triphenylphosphine)palladium(0), and the ratio of theequivalents of the catalyst to the equivalents of the compound is about1:20.

The solvent can be an aqueous solvent, or a mixture of water and anorganic solvent, wherein the organic solvent is selected from methanol,ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol,tertiary butanol, benzene, toluene, tetrahydrofuran, dimethylformamide,1,2-diethyl ether, dimethoxyethane, diisopropyl ether,methyltertiarybutyl ether, methoxymethyl ether, 2-methoxyethyl ether,1,4-dioxane, 1,3-dioxolane, and mixtures thereof. In particularembodiments, the solvent is a mixture of water, toluene, and ethanol,for example, in a ratio of about 1:3:1 by volume.

The process can be carried out at a temperature of about 20° C. to about100° C. In some embodiments, the process is earned out at the refluxtemperature of the solvent.

Other reaction conditions for the Suzuki-type coupling reactions of theinvention are identified by those of skill in the art, e.g., byreference to Suzuki & Brown, Organic Synthesis Via Boranes Volume 3:Suzuki Coupling, (Aldrich, 2003).

In some embodiments, Het-CH₂R³ is:

For example, Het-CH₂R³ can be:

In some embodiments, the process of the invention involves compoundswhere: A is selected from phenyl and pyridyl; B is selected from phenyland pyridyl; m is 0, 1, or 2; and n is 0, 1, or 2.

For example, he process of the invention involves compounds where: A isselected from phenyl and pyridyl; B is phenyl; m is 0; and n is 0, 1, or2.

In certain embodiments, R³ is —NHC(O)R⁴.

In certain embodiments, wherein R⁴ is selected from —CH³, —CHCl₂, —CF₂H,—CH₂Cl, —CFH₂, —CFHCl, —CCl₃, and —CF₃. For example, R⁴ can be —CH₃,—CF₂H, or —CCl₂H.

The process of the invention relates to compounds where R³ is selectedfrom triazole, tetrazole, oxazole, and isoxazole. For example, R³ can betriazole. R³ can be [1,2,3]triazol-1-yl.

In certain embodiments, R¹⁰ is H and t is 0.

In certain embodiments, s can be 1.

In certain embodiments, R¹¹ can be H.

In certain embodiments, Z is selected from I, trifluoromethanesulfonate,and p-toluenesulfonate. For example, Z can be I.

In certain embodiments, Q is —B(OH)₂. In other embodiments, Q is:

In further embodiments, Q is —BF₂.KF.

In some embodiments of the invention, X is selected frompara-methoxybenzyl, para-toluenesulfonyl, trimethylsilyl, anddiphenylphosphoryl. For example, X can be para-methoxybenzyl.

The solvent of (Step 1) can be, for example, toluene, dimethylformamide,dioxane, or tetrahydrofuran. For example, the solvent of (Step 1) istoluene.

(Step 1) can be carried out, for example, at a temperature between about60° C. and about 130° C. For example, (Step 1) is carried out at atemperature between about 80° C. and about 120° C. (Step 1) can becarried out at a temperature of about 100° C.

In some embodiments, (Step 1) is carried out in the presence of a coppercatalyst at a temperature of about 25° C. For example, the coppercatalyst can be a copper (I) catalyst. The copper (I) catalyst can beselected from CuCl, CuBr, CuI, CuOAc, and Cu₂SO4 and mixtures thereof.In some embodiments, the (Step 1) copper catalyst is CuI.

The reducing agent of (Step 2) can be a boron reducing agent or acombination of a palladium catalyst and hydrogen. In one embodiment, thereducing agent of (Step 2) is a boron reducing agent, and can be sodiumborohydride, sodium cyanoborohydride, sodium acetate borohydride, ormixtures thereof. For example, the boron reducing agent of (Step 2) issodium acetate borohydride. In another embodiment, the reducing agent of(Step 2) is a combination of a palladium catalyst and hydrogen. Forexample, the palladium catalyst of (Step 2) is a palladium (0) catalyst.The palladium (0) catalyst of (Step 2) can be a palladium (0) on carboncatalyst.

The solvent of (Step 2) or (Step 2-1) can be, for example, methanol,ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol,tertiary butanol, dichloromethane, 1,1,-dichloroethane, tetrahydrofuran,dimethylformamide or mixtures thereof. For example, the solvent of (Step2) or (Step 2-1) can be tetrahydrofuran.

The base of (Step 2-1) can be, for example, potassium carbonate, sodiumcarbonate, sodium methoxide, sodium ethoxide, potassium fluoride,triethylamine, diisopropylethylamine, or mixtures thereof. For example,the base of (Step 2-1) can be potassium carbonate.

The base of (Step 3) can be, for example, selected from alkali metalhydroxides, alkali metal carbonates, alkali metal fluorides, trialkylamines, and mixtures thereof. For example, the base of (Step 3) can beselected from potassium carbonate, sodium carbonate, sodium methoxide,sodium ethoxide, potassium fluoride, triethylamine,diisopropylethylamine, and mixtures thereof. For example, the base of(Step 3) can be potassium carbonate. In one embodiment, the ratio ofequivalents of base of (Step 3) to equivalents of compound (VI) orcompound (VI-a) is about 3:1.

The palladium catalyst of (Step 3) can be a ligand coordinated palladium(0) catalyst. For example, the palladium catalyst of (Step 3) can be atetrakis (trialkylphosphine) palladium (0) or atetrakis(triarylphosphine) palladium (0) catalyst. For example, thepalladium catalyst of (Step 3) can be tetrakis(triphenylphosphine)palladium (0). In one embodiment, in (Step 3) the ratio of theequivalents of coordinated palladium (0) catalyst (e.g.,tetrakis(triphenylphosphine) palladium (0)) to the equivalents ofcompound (VI) or compound (VI-a) is about 1:20.

The solvent of (Step 3) can include an aqueous solvent. For example, thesolvent of (Step 3) can include a mixture of water and an organicsolvent, wherein the organic solvent is selected from methanol, ethanol,propanol, isopropanol, butanol, isobutanol, secondary butanol, tertiarybutanol, benzene, toluene, tetrahydrofuran, dimethylformamide,1,2-diethyl ether, dimethoxyethane, diisopropyl ether,methyltertiarybutyl ether, methoxymethyl ether, 2-methoxyethyl ether,1,4-dioxane, and 1,3-dioxolane, or mixtures thereof. The solvent of(Step 3) can include a mixture of water, toluene, and ethanol. Forexample, the solvent of (Step 3) can include a mixture of water,toluene, and ethanol in a ratio of about 1:3:1 by volume.

(Step 3) can be carried out at a temperature between about 20° C. andabout 100° C. For example, (Step 3) is carried out at the refluxtemperature of the solvent.

The acid of (Step 3-1) can be, for example, acetic acid, adipic acid,ascorbic acid, citric acid, 2,5-dihydroxybenzoic acid,2,3,4,5-tetrahydroxyhexane-1,6-dicarboxylic acid, glutamic acid,glycolic acid, benzenesulfonic acid, 1,2-ethanedisulfonic acid,ethanesulfonic acid, gluconic acid, glutamic acid, hippuric acid,hydrochloric acid, gluconic acid, maleic acid, malic acid, malonic acid,naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,2-disulfonic acid, oxalic acid, phosphoric acid, citricacid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,trifluoroacetic acid, or mixtures thereof. For example, the acid of(Step 3-1) can be hydrochloric acid.

The solvent of (Step 3-1) can be methanol, ethanol, propanol,isopropanol, butanol, isobutanol, secondary butanol, tertiary butanol,benzene, toluene, tetrahydrofuran, dimethylformamide, 1,2-diethyl ether,dimethoxyethane, diisopropyl ether, methyltertiarybutyl ether,methoxymethyl ether, 2-methoxyethyl ether, 1,4-dioxane, 1,3-dioxolane,ethyl acetate, dichloromethane, 1,1-dichloroethane, or mixtures thereof.For example, the solvent of (Step 3-1) can be a mixture of ethyl acetateand methanol.

The acid of (Step 4) can be, for example, trifluoroacetic acid.

The acid of (Step 5) can be, for example, acetic acid, adipic acid,ascorbic acid, citric acid, 2,5-dihydroxybenzoic acid,2,3,4,5-tetrahydroxyhexane-1,6-dicarboxylic acid, glutamic acid,glycolic acid, benzenesulfonic acid, 1,2-ethanedisulfonic acid,ethanesulfonic acid, gluconic acid, glutamic acid, hippuric acid,hydrochloric acid, gluconic acid, maleic acid, malic acid, malonic acid,naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,2-disulfonic acid, oxalic acid, phosphoric acid, citricacid, sulfuric acid, tartaric acid, p-toluenesulfonic acid,trifluoroacetic acid, or mixtures thereof. For example, the acid of(Step 5) can be hydrochloric acid.

The protecting group reagent of (Step 2-1) is selected such that the—N-Protecting Group of Compound (VI-a-P) is selected from a) N-benzyl,b) N-t-butyldimethylsilyl, c) N-t-butdyldiphenylsilyl, d)N-t-butyloxycarbonyl, e) N-p-methoxybenzyl, f) N-methoxymethyl, g)N-tosyl, h) N-trifluoroacetyl, i) N-trimethylsilyl, j)N-fluorenyl-methyloxycarbonyl, k) N-2-trimethylsilyl-ethyoxycarbonyl, l)N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, m) N-allyloxycarbonyl, and n)N-benzyloxycarbonyl. For example, the protecting group reagent of (Step2-1) can be di-tert-butyl carbonate.

In some embodiments of the invention, Compound (VII) is selected from:

In some embodiments of the invention, Compound (VII-a) is selected from:

In some embodiments, Compound (V) has the formula:

In some embodiments, Compound (V-a) has the formula:

In yet further embodiments, the present invention also relates to and isintended to include the intermediate compounds useful in the processesof the present invention.

The invention relates to a compound corresponding to the structure

or a pharmaceutically acceptable salt thereof, wherein each R²⁰ isindependently C_(1-C) ₆ alkyl or —O—(C₁-C₆ alkyl).

In one embodiment, R²⁰ is methyl.

Table 1 includes exemplary compounds that can be synthesized accordingto the processes of the invention.

TABLE 1 Compound Number Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

In the foregoing table, a bolded bond is shown to indicate a particularstereochemistry at a chiral center. An unbolded bond from a chiralcenter indicates that the substituent can be either an enantiomer, i.e.,R or S, or a mixture of both. Furthermore, the chemical names areprovided below each compound for convenience and are not intended tolimit the indicated chemical structures. To the extent that there is adiscrepancy between the chemical name and the structure of a compound,the structure of the compound shall govern. Also, depending on theconventions and choices available, more than one chemical name can begiven to a particular chemical structure. As a nonlimiting example,Compound 8 is drawn with stereochemistry indicated for the methylacetamide substituent on the oxazolidinone ring, but with nostereochemistry indicated for the methyl substituent on the chiralcenter of the methylene group connecting the triazole ring and the N ofthe remainder of the molecule. Compound 8 is named indicating the “5S”stereochemistry at the chiral carbon center at which the acetamidesubstituent is attached. However, Compound 1 is also named with a“(R/S)” designation, indicating that the stereochemistry is undefined orthe compound is racemic with respect to the methyl substituent, where nostereochemistry is indicated.

Table 2 illustrates the various chemical components, i.e. theaminoalkyne compound, oxazolidinone compound, and aldehyde compound usedin the synthesis of the compounds of Table 1.

TABLE 2 Compound Oxazolidinone No. Aminoalkyne Compound CompoundAldehyde Compound 1

2

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

3. Examples

Embodiments of the present invention are described in the followingexamples, which are meant to illustrate, not to limit, the scope andnature of the invention.

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230-400mesh) unless otherwise noted.

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below:

-   hr=hour(s)-   min=minute(s)-   mol=mole(s)-   mmol=millimole(s)-   M=molar-   μM=micromolar-   g=gram(s)-   μg=microgram(s)-   rt=room temperature-   L=liter(s)-   mL=milliliter(s)-   Et₂O=diethyl ether-   THF=tetrahydrofuran-   DMSO=dimethyl sulfoxide-   EtOAc=ethyl acetate-   Et₃N=triethylamine-   i-Pr₂NEt=diisopropylethylamine-   CH₂Cl₂=methylene chloride-   CHCl₃=chloroform-   CDCl₃=deuterated chloroform-   CCl₄=carbon tetrachloride-   MeOH=methanol-   CD₃OD=deuterated methanol-   EtOH=ethanol-   DMF=dimethylformamide-   BOC=t-butoxycarbonyl-   CBZ=benzyloxycarbonyl-   LCMS=liquid chromatography mass spectroscopy-   TBS=t-butyldimethylsilyl-   TBSCl=t-butyldimethylsilyl chloride-   TFA=trifluoroacetic acid-   TMS=trimethylsilyl (when a substituent in a chemical structure) or    tetramethylsilane-   DBU=diazabicycloundecene-   TBDPSCl=t-butyldiphenylchlorosilane-   Hunig's Base=N,N-diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   CuI=copper (I) iodide-   MsCl=methanesulfonyl chloride-   NaN₃=sodium azide-   Na₂SO₄=sodium sulfate-   NaHCO₃=sodium bicarbonate-   NaOH=sodium hydroxide-   MgSO₄=magnesium sulfate-   K₂CO₃=potassium carbonate-   KOH=potassium hydroxide-   NH₄OH=ammonium hydroxide-   NH₄Cl=ammonium chloride-   SiO₂=silica-   Pd—C=palladium on carbon-   Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium    (II)

Example 1 Synthesis of Compound 1

Compound 1 and its hydrochloride salt are synthesized according to thefollowing Scheme:

4-Methoxybenzyl Azide 1001. A solution of 4-methoxybenzyl chloride 1000(51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solidsodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and theresulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MSshowed that the reaction was complete, the reaction mixture was quenchedwith H₂O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature.The two layers were separated, and the aqueous layer was extracted withEtOAc (200 mL). The combined organic extracts were washed with H₂O(2×200 mL) and saturated NaCl aqueous solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil,which by HPLC and ¹H NMR was found to be essentially pure and wasdirectly used in the subsequent reaction without further purifications.For 4-methoxybenzyl azide 1001: ¹H NMR (300 MHz, CDCl₃) δ 3.84 (s, 3H,ArOCH₃), 4.29 (s, 2H, Ar—CH₂), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H,J=7.8 Hz).

C-[1-(4-Methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-Methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004). A solution of 4-methoxybenzyl azide 1001 (61.2 g, 375.5 mmol) intoluene (188 mL) was heated with propargylamine 1002 (commerciallyavailable, 30.97 g, 38.6 mL, 563.0 mmol, 1.5 equiv) at 25° C., and theresulting reaction mixture was warmed up to gentle reflux at 100-110° C.for 21 h. When TLC and HPLC/MS showed that the reaction was complete,the reaction mixture was cooled down to room temperature before beingconcentrated in vacuo to remove the excess amount of propargylamine andsolvent. The oily residue was then treated with 30% ethyl acetate-hexane(v/v, 260 mL), and the resulting mixture was warmed up to reflux andstirred at reflux for 30 min before being cooled down to roomtemperature for 1 h. The pale-yellow solids were then collected byfiltration, washed with 30% ethyl acetate-hexane (v/v, 2×100 mL), anddried in vacuo at 40° C. for overnight to afford the crude,cycloaddition product (78.8 g, 81.75 g theoretical, 96.4%) as a mixtureof two regioisomers,C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004), in a ratio of 1.2 to 1 by ¹H NMR. The crude cycloaddition productwas found to be essentially pure and the two regioisomers were notseparated before being used directly in the subsequent reaction withoutfurther purification. For 1003 and 1004: ¹H NMR (300 MHz, DMSO-d₆) δ1.82 (br. s, 2H, NH₂), 3.72 and 3.73 (two s, 3H, Ar—OCH₃), 5.47 and 5.53(two s, 2H, ArCH₂), 6.89 and 6.94 (two d, 2H, J=8.7 Hz, Ar—H), 7.17 and7.29 (two d, 2H, J=8.7 Hz, Ar—H), 7.58 and 7.87 (two br. s, 1H,triazole-CH); C₁₁H₁₄N₄O, LCMS (EI) m/e 219 (M⁺+H) and 241 (M⁺+Na).

4-({tert-Butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-Butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009). Method A. A solution of the regioisomericC-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004, 20.0 g, 91.74 mmol) in 1,2-dichloroethane (DCE, 280 mL) wastreated with 4-formylphenylboronic acid 1005 (commercially available,12.39 g, 82.57 mmol, 0.9 equiv) at room temperature, and the resultingreaction mixture was stirred at room temperature for 10 min. Sodiumtriacetoxyborohydride (NaB(OAc)₃H, 29.2 g, 137.6 mmol, 1.5 equiv) wasthen added to the reaction mixture in three portions over the period of1.5 h at room temperature, and the resulting reaction mixture wasstirred at room temperature for an additional 3.5 h. When TLC andHPLC/MS showed that the reductive animation reaction was complete, thereaction mixture was concentrated in vacuo. The residue, which containeda regioisomeric mixture of4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid as the reductive animation products (1006 and 1007), was thentreated with tetrahydrofuran (THF, 100 mL) and water (H₂O, 100 mL). Theresulting solution was subsequently treated with solid potassiumcarbonate (K₂CO₃, 37.98 g, 275.2 mmol, 3.0 equiv) and di-tert-butyldicarbonate (BOC₂O, 20.02 g, 91.74 mmol, 1.0 equiv) at room temperatureand the reaction mixture was stirred at room temperature for 2 h. WhenTLC and HPLC/MS showed that the N-BOC protection reaction was complete,the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) andwater (H₂O, 100 mL). The two layers were separated, and the aqueouslayer was extracted with ethyl acetate (50 mL). The combined organicextracts were washed with H₂O (50 mL), 1.5 N aqueous HCl solution (2×100mL), H₂O (100 mL), and saturated aqueous NaCl solution (100 mL), driedover MgSO₄, and concentrated in vacuo. The crude, regioisomeric4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 35.98 g, 37.32 g, 96.4%) was obtained as apale-yellow oil, which solidified upon standing at room temperature invacuo. This crude material was directly used in the subsequent reactionwithout further purification. For 1008 and 1009: ¹H NMR (300 MHz,DMSO-d₆) δ 1.32 and 1.37 (two br. s, 9H, COOC(CH₃)₃), 3.70, 3.73 and3.74 (three s, 3H, Ar—OCH₃), 4.07-4.39 (m, 4H), 5.49 and 5.52 (two s,2H), 6.70-8.04 (m, 9H, Ar—H and triazole-CH); C₂₃H₂₉BN₄O₅, LCMS (EI) m/e453 (M⁺+H) and 475 (M⁺+Na).

Method B. A solution of the regioisomericC-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004, 20.06 g, 92.0 mmol) in tetrahydrofuran (THF, 300 mL) was treatedwith 4-formylphenylboronic acid (13.11 g, 87.4 mmol, 0.95 equiv) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)₃H, 29.25g, 138.0 mmol, 1.5 equiv) was then added to the reaction mixture inthree portions over the period of 1.5 h at room temperature, and theresulting reaction mixture was stirred at room temperature for anadditional 3.5 h. When TLC and HPLC/MS showed that the reductiveanimation reaction was complete, the reaction mixture, which contained aregioisomeric mixture of4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid as the reductive animation products (1006 and 1007), was thentreated with water (H₂O, 200 mL). The resulting aqueous solution wassubsequently heated with solid potassium carbonate (K₂CO₃, 38.0 g, 276mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC₂O, 20.08 g, 92 mmol,1.0 equiv) at room temperature and the reaction mixture was stirred atroom temperature for 2 h. When TLC and HPLC/MS showed that the N-BOCprotection reaction was complete, the reaction mixture was treated withethyl acetate (EtOAc, 150 mL) and water (H₂O, 100 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(50 mL). The combined organic extracts were washed with H₂O (50 mL), 1.5N aqueous HCl solution (2×100 mL), H₂O (100 mL), and saturated aqueousNaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo. Thecrude,4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 38.45 g, 39.50 g, 97.3%) was obtained as apale-yellow oil, which solidified upon standing at room temperature invacuo. This crude material was found to be essentially identical inevery comparable aspect as the material obtained from Method A and wasdirectly used in the subsequent reaction without further purification.

(5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester and(5S)-{4′-[5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamicacid tert-butyl ester (1011 and 1012).

A suspension of the crude regioisomeric mixture of4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 37.62 g, 83.23 mmol) andN-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1010, 28.32 g, 74.9 mmol, 0.90 equiv) in toluene (150 mL) was treatedwith powder K₂CO₃ (34.45 g, 249.7 mol, 3.0 equiv), EtOH (50 mL), and H₂O(50 mL) at 25° C., and the resulting mixture was degassed three timesunder a steady stream of Argon at 25° C. Pd(PPh₃)₄ (866 mg, 0.749 mmol,0.01 equiv) was subsequently added to the reaction mixture, and theresulting reaction mixture was degassed three times again under a steadstream of Argon at 25° C. before being warmed up to gentle reflux for 18h. When TLC and HPLC/MS showed the coupling reaction was complete, thereaction mixture was cooled down to room temperature before beingtreated with H₂O (100 mL) and ethyl acetate (100 mL). The two layerswere then separated, and the aqueous layer was extracted with EtOAc (100mL). The combined organic extracts were washed with H₂O (50 mL), 1.5 Naqueous HCl solution (2×150 mL), H₂O (100 mL), and the saturated aqueousNaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo. Theresidual oil was solidified upon standing at room temperature in vacuoto afford the crude,(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-y]methyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester (1011) and(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamicacid tert-butyl ester (1012) as a regioisomeric mixture. This crudeproduct (43.36 g, 49.28 g theoretical, 88%) was used directly in thesubsequent reaction without further purification. For the mixture of1011 and 1012: ¹H NMR (300 MHz, DMSO-d₆) δ 1.35 and 1.38 (two br. s, 9H,COO(CH₃)₃), 1.85 (s, 3H, COCH₃), 3.45 (t, 2H, J=5.4 Hz), 3.73 and 3.76(two s, 3H, Ar—OCH₃), 3.79 (dd, 1H, J=6.6, 9.1 Hz), 4.18 (t, 1H, J=9.1Hz), 4.35-4.43 (m, 4H), 4.73-4.81 (m, 1H), 5.50 (br. s, 2H), 6.90 and6.98 (two d, 2H, J=8.7 Hz), 7.28 and 7.32 (two d, 2H, J=8.7 Hz), 7.35(dd, 2H, J=2.2, 8.6 Hz), 7.42 (dd, 1H, J=2.2, 8.6 Hz), 7.49-7.63 (m, 4H,aromatic-H), 7.90 and 7.99 (two br. s, 1H, triazole-CH), 8.29 (t, 1H,J=5.8 Hz, NHCOCH₃); C₃₅H₃₉FN₆O₆, LCMS (EI) m/e 659 (M⁺+H) and 681(M⁺+Na).

(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamideHydrochloride (1013) and(5S)-N-{3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H--[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamideHydrochloride (1014). A solution of a regioisomeric mixture of(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester and(5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-carbamicacid tert-butyl ester (1011 and 1012, 37.28 g, 56.65 mmol) in ethylacetate (EtOAc, 150 mL) and methanol (MeOH, 30 mL) was treated with asolution of 4 N hydrogen chloride in 1,4-dioxane (113.3 mL, 453.2 mmol,8.0 equiv) at room temperature, and the resulting reaction mixture wasstirred at room temperature for 12 h. When TLC and HPLC/MS showed thatthe N-BOC deprotection reaction was complete, the solvents were removedin vacuo. The residue was then suspended in 250 mL of 5% methanol (MeOH)in acetonitrile (CH₃CN), and the resulting slurry was stirred at roomtemperature for 1 h. The solids were then collected by filtration,washed with toluene (2×100 mL) and 5% methanol in acetonitrile (2×50mL), and dried in vacuo to afford a regioisomeric mixture of the crude,(5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamidehydrochloride and(5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamidehydrochloride (1013 and 1014, 30.0 g, 33.68 g theoretical, 89.1% yield)as off-white crystals in a ratio of 1.2 to 1. This material was found by¹H NMR and HPLC/MS to be essentially pure and was directly used in thesubsequent reactions without further purification. For the regioisomericmixture of 1013 and 1014: ¹H NMR (300 MHz, DMSO-d₆) δ 1.84 (s, 3H,COCH₃), 3.44 (t, 2H, J=5.4 Hz), 3.71 and 3.74 (two s, 3H, Ar—OCH₃), 3.80(dd, 1H, J=6.6, 9.1 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.23-4.30 (m, 4H),4.73-4.80 (m, 1H), 5.58 and 5.70 (two s, 2H), 6.88 and 6.93 (two d, 2H,J=8.7 Hz), 7.15 and 7.32 (two d, 2H, J=8.7 Hz), 7.43 (dd, 2H, J=2.2, 8.6Hz), 7.52-7.62 (m, 6H, aromatic-H), 8.28 (s, 1H, triazole-CH), 8.32 (t,1H, J=5.8 Hz, NHCOCH₃), 9.91 and 10.32 (two br. s, 2H, ArCH₂N⁺H₂);C₃₀H₃₁FN₆O₄, LCMS (EI) m/e 559 (M⁺+H) and 581 (M⁺+Na).

(5S)-N-[3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamidehydrochloride (1 hydrochloride salt). A solution of the cruderegioisomeric mixture of(5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamidehydrochloride and(5S)-1H-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamidehydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroaceticacid(TFA, 150 mL) was warmed up to 65-70° C., and the resulting reactionmixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showedthat the deprotection reaction was complete, the solvents were removedin vacuo. The residual solids were then treated with ethyl acetate(EtOAc, 100 mL) and H₂O (150 mL) before being treated with a saturatedaqueous solution of sodium carbonate (30 mL) at room temperature. Theresulting mixture was then stirred at room temperature for 1 h beforethe solids were collected by filtration, washed with EtOAc (2×50 mL) andH₂O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude,(5S)-N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl)-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-whitepowders, which by HPLC/MS and ¹H NMR was found to be one pureregioisomer and this regioisomer was found to be identical as thematerial obtained from deprotection of 1013 alone by the same method.For 1 as the free base: ¹H NMR (300 MHz, DMSO-d₆) δ 1.85 (s, 3H, COCH₃),3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4,9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H,aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH₃),9.72 (br. s, 2H, ArCH₂N⁺H₂), 15.20 (br. s, 1H, triazole-NH);C₂₂H₂₃FN₆O₃, LCMS (EI) m/e 439 (M⁺+H) and 461 (M⁺+Na).

A suspension of 1 free base (18.0 g, 41.1 mmol) in ethyl acetate (EtOAc,80 mL), and methanol (MeOH, 20 mL) was treated with a solution of 4.0 Nhydrogen chloride in 1,4-dioxane (41.1 mL, 164.4 mmol, 4.0 equiv) atroom temperature, and the resulting mixture was stirred at roomtemperature for 8 h. The solvents were then removed in vacuo, and theresidue was further dried in vacuo before being treated with a mixtureof 10% methanol in acetonitrile (80 mL). The solids were collected byfiltration, washed with 10% MeOH/acetonitrile (2×40 mL), and dried invacuo to afford 1 hydrochloride salt (18.13 g, 19.50 g theoretical, 93%yield) as off-white crystals.

The crude 1 hydrochloride salt can be recrystallized from acetonitrileand water, if necessary, according to the following procedure: Asuspension of the crude 1 hydrochloride salt (50.0 g) in acetonitrile(1250 mL) was warmed up to reflux before the distilled water (H₂O, 280mL) was gradually introduced to the mixture. The resulting clear yellowto light brown solution was then stirred at reflux for 10 min beforebeing cooled down to 45-55° C. The solution was then filtered through aCelite bed at 45-55° C., and the filtrates were gradually cooled down toroom temperature before being further cooled down to 0-5° C. in an icebath for 1 h. The solids were then collected by filtration, washed withacetonitrile (2×50 mL), and dried in vacuo at 40° C. for 24 h to affordthe recrystallized 1 hydrochloride salt (42.5 g, 50.0 g theoretical, 85%recovery) as off-white crystals. For 1: ¹H NMR (300 MHz, DMSO-d₆) δ 1.86(s, 3H, COCH₃), 3.45 (t, 2H, J=5.4 Hz), 3.84 (dd, 1H, J=6.4, 9.2 Hz),4.19 (t, 1H, J=9.1 Hz), 4.24 (br. s, 2H), 4.31 (br. s, 2H), 4.74-4.79(m, 1H), 7.44 (dd, 1H, J=2.2, 8.6 Hz), 7.57-7.66 (m, 6H, aromatic-H),8.17 (s, 1H, triazole-CH), 8.30 (t, 1H, J=5.8 Hz, NHCOCH₃), 9.72 (br. s,2H, ArCH₂N⁺H₂), 15.20 (br. s, 1H, triazole-NH); ¹³C NMR (75 MHz,DMSO-d₆) δ 22.57, 40.69, 41.50, 47.36, 49.23, 71.85, 105.70 (d, J=28.5Hz), 114.14 (d, J=2.9 Hz), 122.29 (d, J=13.3 Hz), 128.82 (d, J=3.0 Hz),130.70, 130.94, 131.0, 131.22, 135.30, 137.92 (br. s), 139.66 (d, J=11.2Hz), 154.11, 159.13 (d, J=243.5 Hz), 170.19; C₂₂H₂₃FN₆O₃—HCl, LCMS (EI)m/e 439 (M⁺+H) and 461 (M⁺+Na).

Synthesis of Oxazolidinone Compound 1010

Oxazolidinone compound 1010 is prepared according to the followingsynthetic scheme.

(3-Fluoro-phenyl)-carbamic acid benzyl ester (1016). A solution of the3-fluoro-phenylamine (1015, 18.7 g, 168.3 mmol) in tetrahydrofuran (THF,150 mL) was treated with potassium carbonate (K₂CO₃, 46.45 g, 336.6mmol, 2.0 equiv) and H₂O (150 mL) before a solution of benzylchloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 mL, 1.1 equiv) in THF(50 mL) was dropwise added into the reaction mixture at room temperatureunder N₂. The resulting reaction mixture was stirred at room temperaturefor 2 h. When TLC showed that the reaction was complete, the reactionmixture was treated with H₂O (100 mL) and ethyl acetate (EtOAc, 100 mL).Tire two layers were separated, and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic extracts were washed with H₂O(2×100 mL) and saturated NaCl aqueous solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The residue was further dried in vacuoto afford the crude, (3-fluoro-phenyl)-carbamic acid benzyl ester (2,39.2 g, 41.23 g theoretical, 95%) as pale-yellow oil, which was found tobe essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1016: ¹H NMR (300 MHz, CDCl₃) δ 5.23(s, 2H, OCH₂Ph), 6.75-6.82 (m, 2H), 7.05 (dd, 1H, J=1.4, 8.2 Hz),7.22-7.45 (m, 6H); C₁₄H₁₂FNO₂, LCMS (EI) m/e 246 (M⁺+H).

(5S)-3-(3-Fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018). Asolution of (3-fluoro-phenyl)-carbamic acid benzyl ester (1016, 39.2 g,160.0 mmol) in anhydrous tetrahydrofuran (THF, 300 mL) was cooled downto −78° C. in a dry-ice-acetone bath before a solution of n-butyllithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv)in hexane was dropwise added at −78° C. under N₂. The resulting reactionmixture was subsequently stirred at −78° C. for 1 h before a solution of(R)-(−)-glycidyl butyrate 1017 (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv)in anhydrous THF (100 mL) was dropwise added into the reaction mixtureat −78° C. under N₂. The resulting reaction mixture was stirred at −78°C. for 30 min before being gradually warmed up to room temperature for12 h under N₂. When TLC and HPLC/MS showed that the reaction wascomplete, the reaction mixture was quenched with H₂O (200 mL), and theresulting mixture was stirred at room temperature for 1 h before ethylacetate (EtOAc, 200 mL) was added. The two layers were separated, andthe aqueous layer was extracted with EtOAc (2×100 mL). The combinedorganic extracts were washed with H₂O (2×100 mL) and saturated NaClaqueous solution (100 mL), dried over MgSO₄, and concentrated in vacuo.The white crystals were precipitated out from the concentrated solutionwhen most of the solvents were evaporated. The residue was then treatedwith 20% EtOAc-hexane (100 mL) and the resulting slurry was furtherstirred at room temperature for 30 min. Tire solids were then collectedby filtration and washed with 20% EtOAc-hexane (2×50 mL) to afford thecrude, (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018,24.4 g, 33.76 g theoretical, 72.3%) as white crystals, which were foundto be essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1018: ¹H NMR (300 MHz, DMSO-d₆) δ3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 1H, J=12.0Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H),7.32-7.56 (m, 3H); C₁₀H₁₀FNO₃, LCMS (EI) m/e 212 (M⁺+H).

(5R)-3-(3-Fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019).A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one(1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) wastreated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at25° C., and the resulting reaction mixture was stirred at 25° C. for 2h. When TLC and HPLC/MS showed that the reaction was complete, thereaction mixture was concentrated in vacuo. The residue was then treatedwith H₂O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and theresulting mixture was stirred at 25° C. for 30 min before being cooleddown to 0-5° C. for 2 h. The white solids were collected by filtration,washed with H₂O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried invacuo to afford the crude,(5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019,15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were foundto be essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1019: ¹H NMR (300 MHz, DMSO-d₆) δ3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd,1H, J=6.3, 9.0 Hz), 4.07(t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s,1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz),7.81 (dd, 1H, J=7.8, 8.7 Hz); C₁₀H₉FINO₃, LCMS (EI) m/e 338 (M⁺+H).

(5R)-Methanesulfonic acid3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020). Asolution of(5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019,25.2 g, 74.8 mmol) in methylene chloride (CH₂Cl₂, 150 mL) was treatedwith triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25°C., and the resulting mixture was cooled down to 0-5° C. beforemethanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv)was dropwise introduced into the reaction mixture at 0-5° C. under N2.The resulting reaction mixture was subsequently stirred at 0-5° C. for 1h under N₂. When TLC and HPLC/MS showed that the reaction was complete,the reaction mixture was quenched with H₂O (100 mL) and CH₂Cl₂ (100 mL).The two layers were separated, and the aqueous layer was extracted withCH₂Cl₂ (100 mL). The combined organic extracts were washed with H₂O(2×100 mL) and saturated NaCl aqueous solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The residue was further dried in vacuoto afford the crude, (5R)-methanesulfonic acid3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020,30.71 g, 31.04 g theoretical, 98.9%) as off-white powders, which wasfound to be essentially pure and was directly used in the subsequentreactions without further purifications. For 1020: C₁₁H₁₁FINO₅S, LCMS(EI) m/e 416 (M⁺+H).

(5R)-2-[3-(3-Fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione(1021). A solution of (5R)-methanesulfonic acid3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020,26.38 g, 63.57 mmol) in anhydrous N,N-dimethylformamide (DMF, 120 mL)was treated with solid potassium pathilimide (12.95 g, 70.0 mmol, 1.1equiv) at 25° C., and the resulting reaction mixture was warmed up to70° C. for 2 h. When TLC and HPLC showed that the reaction was complete,the reaction mixture was cooled down to room temperature before beingquenched with H₂O (400 mL), and the resulting mixture was stirred atroom temperature for 10 min before being cooled down to 0-5° C. for 1 h.The white precipitates were then collected by filtration, washed withwater (3×100 mL), and dried in vacuo to afford the crude,(5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione(1021, 27.85 g, 29.64 g theoretical, 94%) as off-white powders, whichwere found to be essentially pure and was directly used in thesubsequent reactions without further purifications. For 1021:C₁₈H₁₂FIN₂O₄, LCMS (EI) m/e 467 (M⁺+H).

(5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022). Asolution of(5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione(1021, 23.3 g, 50.0 mmol) in ethanol (EtOH, 150 mL) was treated withhydrazine monohydrate (12.52 g, 12.1 mL, 250 mmol, 5.0 equiv) at 25° C.,and the resulting reaction mixture was warmed up to reflux for 2 h.White precipitates were formed while the reaction mixture was refluxed.When TLC and HPLC showed that the reaction was complete, the reactionmixture was cooled down to room temperature before being quenched withH₂O (100 mL). The white precipitates were totally dissolved when waterwas introduced into the reaction mixture and a homogeneous solution wasgenerated. The aqueous solution was then extracted with CH₂Cl₂ (3×200mL), and the combined organic extracts were washed with H₂O (2×100 mL)and saturated NaCl aqueous solution (100 mL), dried over MgSO₄, andconcentrated in vacuo. The residue was further dried in vacuo to affordthe crude (5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one(1022, 16.0 g, 16.8 g theoretical, 95.2%) as white powders, which werefound to be essentially pure and was directly used in the subsequentreactions without further purifications. For 1022: C₁₀H₁₀FIN₂O₂, LCMS(EI) m/e 337 (M⁺+H).

(5S)-N-[3-(3-Fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1010). A suspension of(5S)-5-aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022,16.0 g, 47.6 mmol) in CH₂Cl₂ (150 mL) was treated with triethylamine(TEA, 9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and theresulting reaction mixture was cooled down to 0-5° C. before beingtreated with acetic anhydride (Ac₂O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01equiv) at 0-5° C. under N₂. The resulting reaction mixture wassubsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed thatthe reaction was complete, the reaction mixture was quenched with H₂O(100 mL). The two layers were separated, and the aqueous layer was thenextracted with CH₂Cl₂ (2×50 mL), and the combined organic extracts werewashed with H₂O (2×100 mL) and saturated NaCl aqueous solution (100 mL),dried over MgSO₄, and concentrated in vacuo. The residue was furtherdried in vacuo to afford the crude,(5S)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1010, 17.36 g, 17.99 g theoretical, 96.5%) as white powders, which werefound to be essentially pure and was directly used in the subsequentreactions without further purifications. For 1010: ¹H NMR (300 MHz,DMSO-d₆) δ 1.63 (s, 3H, NHCOCH₃), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H,J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz),7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH₃);C₁₂H₁₂FIN₂O₃, LCMS (EI) m/e 379 (M⁺+H).

Example 2 Synthesis of Compound 2.

Compound 2 is prepared using a reaction scheme analogous to that forcompound 1, using oxazolidinone compound 1025 in place of iodide 1010.

Synthesis of Oxazolidinone Compound 1025

Oxazolidinone compound 1025 is prepared according to the followingreaction scheme which is analogous to that used for the synthesis ofoxazolidinone compound 1010.

(5R)-Methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020). Asolution of(5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one (1019,11.66 g, 34.6 mmol) in methylene chloride (CH₂Cl₂, 80 mL) was treatedwith N,N-diisopropylethylamine (Hunig's base, DIEA, 8.95 g, 12.1 mL,69.2 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooleddown to 0-5° C. before methanesulfonyl chloride (MsCl, 4.36 g, 2.95 mL,38.1 mmol, 1.1 equiv) was dropwise introduced into the reaction mixtureat 0-5° C. under N₂. The resulting reaction mixture was subsequentlystirred at 0-5° C. for 1 h under N₂. When TLC and HPLC/MS showed thatthe reaction was complete, the reaction mixture was quenched with H₂O(60 mL) and CH₂Cl₂ (60 mL). The two layers were separated, and theaqueous layer was extracted with CH₂Cl₂ (60 mL). The combined organicextracts were washed with H₂O (2×60 mL) and saturated NaCl aqueoussolution (40 mL), dried over MgSO₄, and concentrated in vacuo. Theresidue was further dried in vacuo to afford the crude,(5R)-methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 14.0g, 14.36 g theoretical, 97.5%) as off-white powders, which was found tobe essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1020: ¹H NMR (300 MHz, DMSO-d₆) δ3.26 (s, 3H, OSO₂CH₃), 3.83 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=5.4Hz), 4.44-4.54 (m, 2H), 5.01-5.06 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz),7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); C₁₁H₁₁FIN₅S,LCMS (EI) m/e 416 (M⁺+H).

(5R)-5-Azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023). Asolution of (5R)-methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 14.0g, 33.7 mmol) in anhydrous DMF (50 mL) was treated with sodium azide(NaN₃, 4.4 g, 67.5 mmol, 2.0 equiv) at 25° C., and the resulting mixturewas subsequently warmed up to 70-75° C. for 4 h. When TLC and HPLC/MSshowed that the reaction was complete, the reaction mixture was cooleddown to room temperature before being treated with H₂O (100 mL) andEtOAc (100 mL). The two layers were then separated, and the aqueouslayer was extracted with EtOAc (2×50 mL). The combined organic extractswere then washed with water (2×50 mL) and saturated aqueous NaClsolution (50 mL), dried over MgSO₄, and concentrated in vacuo. Theresidue was further dried in vacuo to afford the crude,(5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023,12.08 g, 12.2 g theoretical, 99%) as white powders. For 1023: ¹H NMR(300 MHz, DMSO-d₆) δ 3.67-3.81 (m, 3H), 4.14 (t, 1H, J=5.4 Hz),4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4,8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C₁₀H₈FIN₄O₂, LCMS (EI) m/e363 (M⁺+H).

(5R)-3-(3-Fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one(1024). A solution of(5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023,11.60 g, 32.0 mmol) in anhydrous DMF (50 mL) was treated withtrimethylsilylacetylene (4.70 g, 6.77 mL, 48.0 mmol, 1.5 equiv) at roomtemperature, and the resulting reaction mixture was warmed up to 90-100°C. for 20 h. When TLC and HPLC/MS showed that the cycloaddition reactionwas complete, the reaction mixture was cooled down to room temperaturebefore being concentrated in vacuo. The residue was further dried invacuo to afford the crude,(5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one(1024, 14.72 g, 14.72 g theoretical, 100%) as brown oil, which wasdirectly used in the subsequent reaction without further purification.For 1024: ¹H NMR (300 MHz, DMSO-d₆) δ 0.01 (s, 9H, SiCH₃), 3.67 (dd, 1H,J=6.4, 9.2 Hz), 4.01 (t, 1H, J=5.4 Hz), 4.59 (d, 2H, J=4.9 Hz),4.91-4.94 (m, 1H), 6.88 (dd, 1H, J=2.4, 8.7 Hz), 7.22 (dd, 1H, J=2.4,8.7 Hz), 7.58 (dd, 1H, J=7.5, 8.7 Hz), 7.73 (s, 1H, triazole-H);C₁₅H₁₈FIN4O₂Si, LCMS (EI) m/e 461 (M⁺+H).

(5R)-3-(3-Fluoro-4-iodo-phenyl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one(1025). A solution of the crude(5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one(1024, 14.72 g, 32.0 mmol) in an 1 M solution of tetrabutylammoniumfluoride in THF (TBAF, 128 mL, 128 mmol, 4.0 equiv) was treated withacetic acid (HOAc, 5 mL) at room temperature, and the resulting reactionmixture was stirred at room temperature for 24 h. When TLC and HPLC/MSshowed that the reaction was complete, the solvents were removed invacuo. The residue was treated with H₂O (300 mL) at room temperature andthe resulting mixture was stirred at room temperature for 1 h. Thesolids were collected by filtration, washed with H₂O (2×100 mL) and 20%EtOAc/hexane (2×100 mL), dried in vacuo. The crude,(5R)-3-(3-fluoro-4-iodo-phenyl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one(1025, 11.65 g, 12.416 g theoretical, 93.8%) was obtained as off-whitepowders, which by HPLC/MS and ¹H NMR was found to be essentially pureand was directly used in the subsequent reactions without furtherpurification. For 1025: ¹H NMR (300 MHz, DMSO-d₆) 3.89 (dd, 1H, J=6.4,9.2 Hz), 4.23 (t, 1H, J=5.4 Hz), 4.84 (d, 2H, J=4.9 Hz), 5.12-5.18 (m,1H), 7.14 (dd, 1H, J=2.4, 8.7 Hz), 7.49 (dd, 1H, J=2.4, 8.7 Hz), 7.76(d, 1H, J=1.0 Hz, triazole-H), 7.82 (dd, 1H, J=7.5, 8.7 Hz), 8.17 (d,1H, J=1.0 Hz, triazole-H); C₁₂H₁₀FIN₄O₂, LCMS (EI) m/e 389 (M⁺+H).

Alternate Synthesis for Compound 2

Compound 2 is alternatively prepared using a reaction scheme analogousto that described above, using the TMS-substituted iodide compound 1024in place of iodide 1025. The TMS group is removed in a later step toyield compound 2. It should be noted that compound 1024 can exist as twoisomeric compounds, 1024i and 1024ii, and that the resultingintermediates would correspondingly be produced as isomeric compounds.

The general reaction schemes and syntheses are as follows:

(3-Fluoro-phenyl)-carbamic acid benzyl ester (1016). A solution of the3-fluoro-phenylamine (1015, 18.7 g, 168.3 mmol) in tetrahydrofuran (THF,150 mL) was treated with potassium carbonate (K₂CO₃, 46.45 g, 336.6mmol, 2.0 equiv) and H₂O (150 mL) before a solution of benzylchloroformate (CBZCl, 31.58 g, 185.1 mmol, 26.1 mL, 1.1 equiv) in THF(50 mL) was dropwise added into the reaction mixture at room temperatureunder N₂. The resulting reaction mixture was stirred at room temperaturefor 2 h. When TLC showed that the reaction was complete, the reactionmixture was treated with H₂O (100 mL) and ethyl acetate (EtOAc, 100 mL).The two layers were separated, and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic extracts were washed with H₂O(2×100 mL) and saturated NaCl aqueous solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The residue was further dried in vacuoto afford the crude, desired (3-fluoro-phenyl)-carbamic acid benzylester (1016, 39.2 g, 41.23 g theoretical, 95%) as pale-yellow oil, whichwas found to be essentially pure and was directly used in the subsequentreactions without further purifications. For 1016:

¹H NMR (300 MHz, CDCl₃) δ 5.23 (s, 2H, OCH₂Ph), 6.75-6.82 (m, 2H), 7.05(dd, 1H, J=1.4, 8.2 Hz), 7.22-7.45 (m, 6H); C₁₄H₁₂FNO₂, LCMS (EI) m/e246 (M⁺+H).

(5R)-3-(3-Fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018). Asolution of (3-fluoro-phenyl)-carbamic acid benzyl ester (1016, 39.2 g,160.0 mmol) in anhydrous tetrahydrofuran (THF, 300 mL) was cooled downto −78° C. in a dry-ice-acetone bath before a solution of n-butyllithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv)in hexane was dropwise added at −78° C. under N₂. The resulting reactionmixture was subsequently stirred at −78° C. for 1 h before a solution of(R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) inanhydrous THF (100 mL) was dropwise added into the reaction mixture at−78° C. under N₂. The resulting reaction mixture was stirred at −78° C.for 30 min before being gradually warmed up to room temperature for 12 hunder N₂. When TLC and HPLC/MS showed that the reaction was complete,the reaction mixture was quenched with H₂O (200 mL), and the resultingmixture was stirred at room temperature for 1 h before ethyl acetate(EtOAc, 200 mL) was added. The two layers were separated, and theaqueous layer was extracted with EtOAc (2×100 mL). The combined organicextracts were washed with H₂O (2×100 mL) and saturated NaCl aqueoussolution (100 mL), dried over MgSO₄, and concentrated in vacuo. Thewhite crystals were precipitated out from the concentrated solution whenmost of the solvents were evaporated. The residue was then treated with20% EtOAc-hexane (100 mL) and the resulting slurry was further stirredat room temperature for 30 min. The solids were then collected byfiltration and washed with 20% EtOAc-hexane (2×50 mL) to afford thecrude, desired(5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 24.4g, 33.76 g theoretical, 72.3%) as white crystals, which were found to beessentially pure and was directly used in the subsequent reactionswithout further purifications. For 1018: ¹H NMR (300 MHz, DMSO-d₆) δ;C₁₀H₁₀FNO₃, LCMS (EI) m/e 212 (M⁺+H).

(5R)-3-(3-Fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019).A solution of (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one(1018, 10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) wastreated with N-iodosuccinimide (NIS, 12.03 g, 53.45 mmol, 1.05 equiv) at25° C., and the resulting reaction mixture was stirred at 25° C. for 2h. When TLC and HPLC/MS showed that the reaction was complete, thereaction mixture was concentrated in vacuo. The residue was then treatedwith H₂O (100 mL) and 20% EtOAc-hexane (100 mL) at 25° C., and theresulting mixture was stirred at 25° C. for 30 min before being cooleddown to 0-5° C. for 2 h. The white solids were collected by filtration,washed with H₂O (2×25 mL) and 20% EtOAc-hexane (2×25 mL), and dried invacuo to afford the crude, desired(5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1019,15.1 g, 17.15 g theoretical, 88%) as off-white powders, which were foundto be essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1019: ¹H NMR (300 MHz, DMSO-d₆) δ3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd,1H, J=6.3, 9.0 Hz), 4.07(t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s,1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz),7.81 (dd, 1H, J=7.8, 8.7 Hz); C₁₀H₉FINO₃, LCMS (EI) m/e 338 (M⁺+H).

(5R)-Methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020). Asolution of(5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one (1019,269.6 g, 0.8 mol) in methylene chloride (CH₂Cl₂, 1200 mL) was treatedwith N,N-diisopropylethylamine (Hunig's base, DIEA, 206.8 g, 279 mL, 1.6mol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to0-5° C. before methanesulfonyl chloride (MsCl, 109.97 g, 74.3 mL, 0.96mol, 1.2 equiv) was dropwise introduced into the reaction mixture at0-5° C. under N₂. The resulting reaction mixture was subsequentlystirred at 0-5° C. for 1 h and then gradually warmed up to roomtemperature for 4 h under N₂. When TLC and HPLC/MS showed that thereaction was complete, the reaction mixture was quenched with H₂O (500mL). The resulting mixture was then stirred at room temperature for 30min. before being concentrated in vacuo to remove methylene chloride.When almost all of methylene chloride was removed in vacuo, the residuewas then treated with H₂O (1000 mL). The resulting slurry was stirred atroom temperature for an additional 1 h. The solids were then collectedby filtration, washed with H₂O (2×500 mL), and dried in vacuo at 40° C.for 24 h to afford the crude, desired (5R)-methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 290.0g, 332.0 g theoretical, 87.3%) as off-white powders, which was found tobe essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1020: ¹H NMR (300 MHz, DMSO-d₆) δ3.26 (s, 3H, OSO₂CH₃), 3.83 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=5.4Hz), 4.44-4.54 (m, 2H), 5.01-5.06 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz),7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz);C₁₁H₁₁FINO₅S, LCMS (EI) m/e 416 (M⁺+H).

(5R)-5-Azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023). Asolution of (5R)-methanesulfonic acid3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (5, 290.0 g,698.8 mmol) in anhydrous DMF (700 mL) was treated with sodium azide(NaN₃, 90.84 g, 1.4 mol, 2.0 equiv) at 25° C., and the resulting mixturewas subsequently warmed up to 70-75° C. for 6 h. When TLC and HPLC/MSshowed that the reaction was complete, the reaction mixture was cooleddown to room temperature before being treated with H₂O (1500 mL) and theresulting mixture was stirred at room temperature for 2 h. The solidswere then collected by filtration, washed with H₂O (2×500 mL), and driedin vacuo at 40° C. for 24 h to afford the crude, desired(5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023,248.0 g, 252.97 g theoretical, 98%) as white powders, which was found tobe essentially pure and was directly used in the subsequent reactionswithout further purifications. For 1023: ¹H NMR (300 MHz, DMSO-d₆) δ3.67-3.81 (m, 3H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd,1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5,8.7 Hz); LCMS C₁₀H₈FIN₄O₂, LCMS (EI) m/e 363 (M⁺+H).

(5R)-3-(3-Fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one(1024). A solution of(5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023,248.0 g, 685.0 mmol) in anhydrous THF (600 mL) was heated withtrimethylsilylacetylene (100.9 g, 145.2 mL, 1027.6 mmol, 1.5 equiv) atroom temperature, and the resulting reaction mixture was warmed up toreflux for 12 h. When TLC and HPLC/MS showed that the cycloadditionreaction was complete, the reaction mixture was cooled down to roomtemperature before being concentrated in vacuo. The residue was furtherdried in vacuo to afford the crude, desired(5R)-3-(3-fluoro-4-iodo-phenyl)-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-one(1024, 315.1 g, 315.1 g theoretical, 100%) as brown oil, which wasdirectly used in the subsequent reaction without further purification.For 1024: ¹H NMR (300 MHz, DMSO-d₆) δ 0.01 (s, 9H, SiCH₃), 3.67 (dd, 1H,J=6.4, 9.2 Hz), 4.01 (t, 1H, J=5.4 Hz), 4.59 (d, 2H, J=4.9 Hz),4.91-4.94 (m, 1H), 6.88 (dd, 1H, J=2.4, 8.7 Hz), 7.22 (dd, 1H, J=2.4,8.7 Hz), 7.58 (dd, 1H, J=7.5, 8.7 Hz), 7.73 (s, 1H, triazole-H);C₁₅H₁₈FIN4O₂Si, LCMS (EI) m/e 461 (M⁺+H).

4-Methoxybenzyl Azide 1001. A solution of 4-methoxybenzyl chloride 1000(51.8 g, 331.0 mmol) in anhydrous DMF (200 mL) was treated with solidsodium azide (21.5 g, 331.0 mmol, 1.0 equiv) at 25° C., and theresulting mixture was stirred at 25° C. for 24 h. When TLC and HPLC/MSshowed that the reaction was complete, the reaction mixture was quenchedwith H₂O (400 mL) and ethyl acetate (EtOAc, 400 mL) at room temperature.The two layers were separated, and the aqueous layer was extracted withEtOAc (200 mL). The combined organic extracts were washed with H₂O(2×200 mL) and saturated NaCl aqueous solution (100 mL), dried overMgSO₄, and concentrated in vacuo. The crude 4-methoxybenzyl azide (51.2g, 53.95 g theoretical, 94.9% yield) was obtained as colorless oil,which by HPLC and ¹H NMR was found to be essentially pure and wasdirectly used in the subsequent reaction without further purifications.For 4-methoxybenzyl azide 1001: ¹H NMR (300 MHz, CDCl₃) δ 3.84 (s, 3H,ArOCH₃), 4.29 (s, 2H, Ar—CH₂), 6.96 (d, 2H, J=8.7 Hz), 7.28 (d, 2H,J=7.8 Hz).

C-[1-(4-Methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-Methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004). A solution of 4-methoxybenzyl azide 1001 (61.2 g, 375.5 mmol) intoluene (188 mL) was treated with propargylamine 1002 (commerciallyavailable, 30.97 g, 38.6 mL, 563.0 mmol, 1.5 equiv) at 25° C., and theresulting reaction mixture was warmed up to gentle reflux at 100-110° C.for 21 h. When TLC and HPLC/MS showed that the reaction was complete,the reaction mixture was cooled down to room temperature before beingconcentrated in vacuo to remove the excess amount of propargylamine andsolvent. The oily residue was then treated with 30% ethyl acetate-hexane(v/v, 260 mL), and the resulting mixture was warmed up to reflux andstirred at reflux for 30 min before being cooled down to roomtemperature for 1 h. The pale-yellow solids were then collected byfiltration, washed with 30% ethyl acetate-hexane (v/v, 2×100 mL), anddried in vacuo at 40° C. for overnight to afford the crude,cycloaddition product (78.8 g, 81.75 g theoretical, 96.4%) as a mixtureof two regioisomers,C-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004), in a ratio of 1.2 to 1 by ¹H NMR. The crude cycloaddition productwas found to be essentially pure and the two regioisomers were notseparated before being used directly in the subsequent reaction withoutfurther purification. For 1003 and 1004: ¹H NMR (300 MHz, DMSO-d₆) δ1.82 (br. s, 2H, NH₂), 3.72 and 3.73 (two s, 3H, Ar—OCH₃), 5.47 and 5.53(two s, 2H, ArCH₂), 6.89 and 6.94 (two d, 2H, J=8.7 Hz, Ar—H), 7.17 and7.29 (two d, 2H, J=8.7 Hz, Ar—H), 7.58 and 7.87 (two br. s, 1H,triazole-CH); C₁₁H₁₄N₄O, LCMS (EI) m/e 219 (M⁺+H) and 241 (M⁺+Na).

4-({tert-Butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-Butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009). Method A. A solution of the regioisomericC-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004, 20.0 g, 91.74 mmol) in 1,2-dichloroethane (DCE, 280 mL) was heatedwith 4-formylphenylboronic acid 1005 (commercially available, 12.39 g,82.57 mmol, 0.9 equiv) at room temperature, and the resulting reactionmixture was stirred at room temperature for 10 min. Sodiumtriacetoxyborohydride (NaB(OAc)₃H, 29.2 g, 137.6 mmol, 1.5 equiv) wasthen added to the reaction mixture in three portions over the period of1.5 h at room temperature, and the resulting reaction mixture wasstirred at room temperature for an additional 3.5 h. When TLC andHPLC/MS showed that the reductive animation reaction was complete, thereaction mixture was concentrated in vacuo. The residue, which containeda regioisomeric mixture of4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazo]-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid as the reductive animation products (1006 and 1007), was thentreated with tetrahydrofuran (THF, 100 mL) and water (H₂O, 100 mL). Theresulting solution was subsequently treated with solid potassiumcarbonate (K₂CO₃, 37.98 g, 275.2 mmol, 3.0 equiv) and di-tert-butyldicarbonate (BOC₂O, 20.02 g, 91.74 mmol, 1.0 equiv) at room temperatureand the reaction mixture was stirred at room temperature for 2 h. WhenTLC and HPLC/MS showed that the N-BOC protection reaction was complete,the reaction mixture was treated with ethyl acetate (EtOAc, 150 mL) andwater (H₂O, 100 mL). The two layers were separated, and the aqueouslayer was extracted with ethyl acetate (50 mL). The combined organicextracts were washed with H₂O (50 mL), 1.5 N aqueous HCl solution (2×100mL), H₂O (100 mL), and saturated aqueous NaCl solution (100 mL), driedover MgSO₄, and concentrated in vacuo. The crude, regioisomeric4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 35.98 g, 37.32 g, 96.4%) was obtained as apale-yellow oil, which solidified upon standing at room temperature invacuo. This crude material was directly used in the subsequent reactionwithout further purification. For 1008 and 1009: ¹H NMR (300 MHz,DMSO-d₆) δ 1.32 and 1.37 (two br. s, 9H, COOC(CH₃)₃), 3.70, 3.73 and3.74 (three s, 3H, Ar—OCH₃), 4.07-4.39 (m, 4H), 5.49 and 5.52 (two s,2H), 6.70-8.04 (m, 9H, Ar—H and triazole-CH); C₂₃H₂₉BN₄O₅, LCMS (EI) m/e453 (M⁺+H) and 475 (M⁺+Na).

Method B. A solution of the regioisomericC-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-methylamine andC-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-yl]-methylamine (1003 and1004, 20.06 g, 92.0 mmol) in tetrahydrofuran (THF, 300 mL) was treatedwith 4-formylphenylboronic acid (13.11 g, 87.4 mmol, 0.95 equiv) at roomtemperature, and the resulting reaction mixture was stirred at roomtemperature for 10 min. Sodium triacetoxyborohydride (NaB(OAc)₃H, 29.25g, 138.0 mmol, 1.5 equiv) was then added to the reaction mixture inthree portions over the period of 1.5 h at room temperature, and theresulting reaction mixture was stirred at room temperature for anadditional 3.5 h. When TLC and HPLC/MS showed that the reductiveanimation reaction was complete, the reaction mixture, which contained aregioisomeric mixture of4-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid as the reductive animation products (1006 and 1007), was thenheated with water (H2O, 200 mL). The resulting aqueous solution wassubsequently treated with solid potassium carbonate (K₂CO₃, 38.0 g, 276mmol, 3.0 equiv) and di-tert-butyl dicarbonate (BOC₂O, 20.08 g, 92 mmol,1.0 equiv) at room temperature and the reaction mixture was stirred atroom temperature for 2 h. When TLC and HPLC/MS showed that the N-BOCprotection reaction was complete, the reaction mixture was treated withethyl acetate (EtOAc, 150 mL) and water (H₂O, 100 mL). The two layerswere separated, and the aqueous layer was extracted with ethyl acetate(50 mL). The combined organic extracts were washed with H₂O (50 mL), 1.5N aqueous HCl solution (2×100 mL), H₂O (100 mL), and saturated aqueousNaCl solution (100 mL), dried over MgSO₄, and concentrated in vacuo. Thecrude,4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 38.45 g, 39.50 g, 97.3%) was obtained as apale-yellow oil, which solidified upon standing at room temperature invacuo. This crude material was found to be essentially identical inevery comparable aspect as the material obtained from Method A and wasdirectly used in the subsequent reaction without further purification.

{2′-Fluoro-4′-[2-oxo-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-3-yl]-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester (SC-167-63-1). A suspension of the cruderegioisomeric mixture of4-({tert-butoxycarbonyl-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid and4-({tert-butoxycarbonyl-[3-(4-methoxy-benzyl)-3H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-phenylboronicacid (1008 and 1009, 0.40 g, 0.89 mmol) andN-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1024, 0.37 g, 0.80 mmol, 0.90 equiv) in toluene (3 mL) was treated withpowder K₂CO₃ (0.365 g, 5.31 mol, 3.0 equiv), EtOH (1 mL), and H₂O (1 mL)at 25° C., and the resulting mixture was degassed three times under asteady stream of Argon at 25° C. Pd(PPh₃)₄ (51 mg, 0.09 mmol, 0.05equiv) was subsequently added to the reaction mixture, and the resultingreaction mixture was degassed three times again under a stead stream ofArgon at 25° C. before being warmed up to gentle reflux for 18 h. WhenTLC and HPLC/MS showed the coupling reaction was complete, the reactionmixture was cooled down to room temperature before being treated withH₂O (20 mL) and ethyl acetate (20 mL). The two layers were thenseparated, and the aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with H₂O (20 mL), 1.5 N aqueousHCl solution (2×20 mL), H₂O (20 mL), and the saturated aqueous NaClsolution (20 mL), dried over MgSO₄, and concentrated in vacuo. Theresidual oil was solidified upon standing at room temperature in vacuoto afford the crude{2′-Fluoro-4′-[2-oxo-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-3-yl]-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester (SC-167-63-1) as a regioisomeric mixture. Thiscrude product (0.484 g, 0.592 g theoretical, 82%) was used directly inthe subsequent reaction without further purification. For SC-167-63-1:¹H NMR (300 MHz, CDCl₃) δ 0.299 and 0.31(two s, 9H, Si(CH₃)₃), 1.44 and1.48 (two br. s, 9H, N-BOC), 3.76 and 3.80 (two s, 3H, Ar—OCH₃),3.98-4.01 (dd, 1H, J=3.6, 1.8 Hz), 4.18-4.24 (t, 1H, J=9.0 Hz),4.27-4.50 (m, 4H), 4.79-4.81 (m, 2H), 5.07-5.1 (br. s, 1H), 5.30 and5.42 (two s, 2H), 6.81 and 6.89 (dd, 2H), 7.13-7.54 (m, 10H,aromatic-H), 7.74 (s, 1H, triazole-CH); C₃₈H₄₅FN₈O₅Si, LCMS (EI) m/e 741(M⁺+H) and 763 (M⁺+Na).

(5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-(4-trimethylsiIanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-oneHydrochloride (SC-167-63-2). A solution of a regioisomeric mixture of{2′-Fluoro-4′-[2-oxo-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-3-yl]-biphenyl-4-ylmethyl}-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-carbamicacid tert-butyl ester SC-167-63-1, 0.18 g, 0.24 mmol) in dichloromethane(CH₂Cl₂, 10 mL) and was treated with a solution of 4 N hydrogen chloridein 1,4-dioxane (0.5 mL, 1.9 mmol, 8.0 equiv) at room temperature, andthe resulting reaction mixture was stirred at room temperature for 6 h.When TLC and HPLC/MS showed that the N-BOC deprotection reaction wascomplete, the solvents were removed in vacuo. The residue was thensuspended in 20 mL of 5% methanol (MeOH) in acetonitrile (CH₃CN), andthe resulting slurry was stirred at room temperature for 1 h. The solidswere then collected by filtration, washed with toluene (2×20 mL) and 5%methanol in acetonitrile (2×20 mL), and dried in vacuo to afford aregioisomeric mixture of the crude,(5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-onehydrochloride (SC-167-63-2, 0.14 g, 0154 g theoretical, 90.9% yield) asoff-white crystals. This material was found by ¹H NMR and HPLC/MS to beessentially pure and was directly used in the subsequent reactionswithout further purification. For SC-167-63-2: ¹H NMR (300 MHz, DMSO-d₆)δ 0.24-0.29 (Two, br. s, 9H, Si(CH₃)₃), 3.18 (S, 3H, Ar—OCH₃), 3.46-3.53(br. s, 1H), 3.97 (br. t, 1H), 4.27-4.32 (m, 4H), 4.85-4.86 (two, m,2H), 5.21 ( m, 1H), 5.38 (two br. s, 2H, ArCH₂N⁺H₂), 5.66 and 5.70 (twos, 2H), 6.89 and 6.96 (two d, 2H), 7.16 and 7.24 (two d, 2H), 7.32-7.38(dd, 1H), 7.49-7.88 (m, 6H, aromatic-H), 8.22 (s, 1H, triazole-CH), 8.30(s, 1H, triazole-CH); C₃₃H₃₇FN₈O₃Si, LCMS (EI) m/e 641 (M⁺+H) and 663(M⁺+Na).

(5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one.A solution of3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-(4-trimethylsilanyl-[1,2,3]triazol-1-ylmethyl)-oxazolidin-2-onehydrochloride (SC-167-63-2, 0.22 g, 0.343 mmol) in an 1 M solution oftetrabutylammonium fluoride in THF (TBAF, 1.4 mL, 1.4 mmol, 4.0 equiv)was treated with acetic acid (HOAc, 5.0 mL) at room temperature, and theresulting reaction mixture was stirred at room temperature for 24 h.When TLC and HPLC/MS showed that the reaction was complete, the solventswere removed in vacuo. The residue was treated with H₂O (30 mL) at roomtemperature and the resulting mixture was stirred at room temperaturefor 1 h. The solids were collected by filtration, washed with H₂O (2×10mL) and 20% EtOAc/hexane (2×20 mL), dried in vacuo. The crude, desired(5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one(SC-167-71, 0.17 g, 0.195 g theoretical, 87%) was obtained as off-whitepowders, which by HPLC/MS and ¹H NMR was found to be essentially pureand was directly used in the subsequent reactions without furtherpurification. For SC-167-71: ¹H NMR (300 MHz, DMSO-d₆) 3.73 and 3.75(two, s, 4H,), 3.94-3.97 (m, 1H), 4.29 (t, 1H), 4.85 and 4.87 (dd, 2H),5.15-5.20 (m, 1H), 5.48 (s, 1H), 6.91 and 6.94 (d, 2H), 7.28-7.58 (m,10H, aromatic-H), 7.78 (s, 1H, triazole-H), 7.98 (s, 1H, triazole-H),8.19 (s, 1H, triazole-H); C₃₀H₂₉FN₈O₃, LCMS (EI) m/e 568 (M⁺+H).

(5R)-3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-onehydrochloride (Compound 2 hydrochloride salt). A solution of the cruderegioisomeric mixture of(5R)-3-[2-Fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one(SC-167-71, 0.30 g, 0.528 mmol) in trifluoroacetic acid (TFA, 10 mL) waswarmed up to 65-70° C., and the resulting reaction mixture was stirredat 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotectionreaction was complete, the solvents were removed in vacuo. The residualsolids were then heated with ethyl acetate (EtOAc, 10 mL) and H₂O (15mL) before being treated with a saturated aqueous solution of sodiumcarbonate (30 mL) at room temperature. The resulting mixture was thenstirred at room temperature for 1 h before the solids were collected byfiltration, washed with EtOAc (2×20 mL) and H₂O (2×20 mL), and dried invacuo at 40-45° C. to afford the crude,(5R)-3-(2-Fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-5-[1,2,3]triazol-1-ylmethyl-oxazolidin-2-one(Compound 2 as the free base, 0.18 g, 0.24 g theoretical, 75%) asoff-white powders, which by HPLC/MS and ¹H NMR was found to be one pureregioisomer. For Compound 2 as the free base: ¹H NMR (300 MHz,DMSO-d₆)67 3.71-3.77 (two br. s, 4H, Ar₁CH₂NHCH₂Ar₂), 3.93-3.98 (m, 1H),4.26-4.32 (t, 1H), 4.86 and 4.87 (d, 2H), 5.14-5.22 (m, 1H), 7.35-7.59(m, 7H, aromatic-H), 7.74 and 7.78 (s, 2H, triazole-CH), 8.19 (s, 1H,triazole-CH); C₂₂H₂₁FN₈O₂, LCMS (EI) m/e 449(M⁺+H) and 471 (M⁺+Na).

A suspension of Compound 2 free base (0.18 g, 0.40 mmol) in ethylacetate (EtOAc, 80 mL), and methanol (MeOH, 20 mL) was treated with asolution of 4.0 N hydrogen chloride in 1,4-dioxane at room temperature,and the resulting mixture was stirred at room temperature for 8 h. Thesolvents were then removed in vacuo, and the residue was further driedin vacuo before being treated with a mixture of 10% methanol inacetonitrile (20 mL). The solids were collected by filtration, washedwith 10% MeOH/acetonitrile (2×10 mL), and dried in vacuo to affordCompound 2 hydrochloride salt (0.19 g, 0.194 g theoretical, 98% yield)as off-white crystals.

The crude Compound 2 hydrochloride salt can be recrystallized fromacetonitrile and water, if necessary, according to the followingprocedure: A suspension of the crude 1 hydrochloride salt (2.0 g) inacetonitrile (150 mL) was warmed up to reflux before the distilled water(H₂O, 10 mL) was gradually introduced to the mixture. The resultingclear yellow to light brown solution was then stirred at reflux for 10min before being cooled down to 45-55° C. The solution was then filteredthrough a Celite bed at 45-55° C., and the filtrates were graduallycooled down to room temperature before being further cooled down to 0-5°C. in an ice bath for 1 h. The solids were then collected by filtration,washed with acetonitrile (2×50 mL), and dried in vacuo at 40° C. for 24h to afford the recrystallized Compound 2 hydrochloride salt (1.58 g,2.0 g theoretical, 79% recovery) as off-white crystals. For Compound 2HCl salt: ¹H NMR (300 MHz, DMSO-d₆) δ 3.94-3.99 (m, 1H), 4.22-4.33 (m,1H and 4H), 4.86 and 4.88 (d, 2H), 5.15-5.22 (m, 1H), 7.18-7.69 (m, 7H,aromatic-H), 7.78 (s, 1H, triazole-CH), 8.13 (s, 1H, triazole-CH), 8.21(s, 1H, triazole-CH), 9.99 (br. s, 2H, ArCH₂N⁺H₂), 12.20 (br. s, 1H,triazole-NH); C₂₂H₂₁FN₈O₂-HCl, LCMS (EI) m/e 449 (M⁺+H) and 471 (M⁺+Na).

Example 3 Synthesis of Compound 3.

Compound 3 is prepared using a reaction scheme analogous to that forcompound 1, using oxazolidinone compound 1026 in place of oxazolidinonecompound 1010.

Synthesis of Oxazolidinone Compound 1026

Oxazolidinone compound 1026 is prepared according to the followingreaction scheme which is analogous to that used for the synthesis ofoxazolidione compound 1010.

(5S)-2,2-Difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1026). A suspension of(5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022,5.0 g, 14.88 mmol) in methylene chloride (CH₂Cl₂, 50 mL) was treatedwith difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) andN,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to0-5° C. before being treated with EDCI (4.30 g, 22.32 mmol, 1.5 equiv)at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for1 h before being gradually warmed up to room temperature for 12 h. WhenTLC and HPLC/MS showed that the reaction was complete, the reactionmixture was quenched with H₂O (50 mL) and CH₂Cl₂ (50 mL). The two layerswere then separated, and the aqueous layer was extracted with CH₂Cl₂(2×50 mL). The combined organic extracts were washed H₂O (50 mL) and thesaturated aqueous NaCl solution (50 mL), dried over MgSO₄, andconcentrated in vacuo to afford the crude(5S)-2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide(1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which byHPLC/MS and ¹H NMR was found to be essentially pure and was directlyused in the subsequent reactions without further purification. For 1026:¹H NMR (300 MHz, DMSO-d₆) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3,9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52Hz, —CHCF₂), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz),7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C₁₂H₁₀F₃IN₂O₃,LCMS (EI) m/e 415 (M⁺+H), 456 (M⁺+H+CH₃CN).

Example 4 Synthesis of Compound 4.

Compound 4 can be prepared using a reaction scheme analogous to that forcompound 1, using oxazolidinone compound 1027 in place of oxazolidinonecompound 1010.

Synthesis of Oxazolidionone Compound 1027

Oxazolidinone compound 1027 can be prepared using a reaction schemeanalogous to that for oxazolidinone compound 1026, in which compound1022 is reacted with dichloroacetic acid or dichloroacetic anhydride toproduce oxazolidinone compound 1027.

Example 5 Synthesis of Compound 5

Compound 5 can be prepared using a reaction scheme analogous to that forcompound 1, using 1-amino-4-pentyne 1028 in place of propargyl amine1002.

Synthesis of 1028

Compound 1028 can be made using standard chemistry procedures, startingwith 1-hydroxy-4-pentyne (commercially available from Aldrich),converting this hydroxyl compound to its mesylate (mesyl chloride,Hunig's base, dichloromethane), converting the mesylate to the azide(sodium azide, tetrahydrofuran/dimethylformamide), and reduction of theazide to the amine (triphenylphosphine, tetrahydrofuran).

Example 6 Synthesis of Compound 6

Compound 6 can be prepared using a reaction scheme analogous to that forcompound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002.

Example 7 Synthesis of Compound 7

Compound 7 can be prepared using a reaction scheme analogous to that forcompound 1, using N-methyl-1-amino-2-propyne (also known asN-methyl-propargyl amine (commercially available from Aldrich) 1030 inplace of propargyl amine 1002.

Example 8 Synthesis of Compound 8

Compound 8 can be prepared using a reaction scheme analogous to that forcompound 1, using 1-amino-1-methyl-2-propyne 1031 (commerciallyavailable from AB Chem Inc.) in place of propargyl amine 1002.

Example 9 Synthesis of Compound 9

Compound 9 can be prepared using a reaction scheme analogous to that forcompound 1, using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-phenylacetaldehyde 1032(which can be made by reduction of the corresponding carboxyl acid) inplace of 4-formylphenylboronic acid 1005.

Example 10 Synthesis of Compound 10

Compound 10 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002 and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-phenylacetaldehyde 1032(which can be made by reduction of the corresponding carboxyl acid) inplace of 4-formylphenylboronic acid 1005.

Example 11 Synthesis of Compound 11

Compound 11 can be prepared using a reaction scheme analogous to thatfor compound 1, using oxazolidinone compound 1033 (synthesis describedin PCT application No. WO 99/10342, to Zeneca Limited, published Mar. 4,1999) in place of oxazolidinone compound 1010.

Example 12 Synthesis of Compound 12

Compound 12 can be prepared using a reaction scheme analogous to thatfor compound 1, using oxazolidinone compound 1034 in place ofoxazolidinone compound 1010. Oxazolidinone compound 1034 can be preparedin an analogous manner to oxazolidinone 1025 using3,5-difluorophenylamine in place of 3-fluorophenylamine 1015.

Example 13 Synthesis of Compound 13

Compound 13 can be prepared using a reaction scheme analogous to thatfor compound 1, using oxazolidinone compound 1035 in place ofoxazolidinone compound 1010. Oxazolidinone compound 1035 can be preparedin an analogous maimer to oxazolidinone 1026 using3,5-difluorophenylamine in place of 3-fluorophenylamine 1015.

Example 14 Synthesis of Compound 14

Compound 14 can be prepared using a reaction scheme analogous to thatfor compound 1, using oxazolidinone compound 1036 in place ofoxazolidinone compound 1010. Oxazolidinone compound 1036 can be preparedin an analogous manner to oxazolidinone 1027 using3,5-difluorophenylamine in place of 3-fluorophenylamine 1015.

Example 15 Synthesis of Compound 15

Compound 15 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-4-pentyne 1028 in place of propargyl amine1002, and oxazolidinone compound 1033 (synthesis described in PCTapplication No. WO 99/10342, to Zeneca Limited, published Mar. 4, 1999)in place of oxazolidinone compound 1010.

Example 16 Synthesis of Compound 16

Compound 16 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002, and oxazolidinonecompound 1033 (synthesis described in PCT application No. WO 99/10342,to Zeneca Limited, published Mar. 4, 1999) in place of oxazolidinonecompound 1010.

Example 17 Synthesis of Compound 17

Compound 17 can be prepared using a reaction scheme analogous to thatfor compound 1, using N-methyl-1-amino-2-propyne (also known asN-methyl-propargyl amine (commercially available from Aldrich) 1030 inplace of propargyl amine 1002, and oxazolidinone compound 1033(synthesis described in PCT application No. WO 99/10342, to ZenecaLimited, published Mar. 4, 1999) in place of oxazolidinone compound1010.

Example 18 Synthesis of Compound 18

Compound 18 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-1-methyl-2-propyne 1031 in place ofpropargyl amine 1002, and oxazolidinone compound 1033 (synthesisdescribed in PCT application No. WO 99/10342, to Zeneca Limited,published Mar. 4, 1999) in place of oxazolidinone compound 1010.

Example 19 Synthesis of Compound 19

Compound 19 can be prepared using a reaction scheme analogous to thatfor compound 1, using oxazolidinone compound 1033 (synthesis describedin PCT application No. WO 99/10342, to Zeneca Limited, published Mar. 4,1999) in place of oxazolidinone compound 1010, and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-phenylacetaldehyde 1032(which can be made by reduction of the corresponding carboxyl acid) inplace of 4-formylphenylboronic acid 1005.

Example 20 Synthesis of Compound 20

Compound 20 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002, oxazolidinone compound1033 (a synthesis which is described in PCT application No. WO 99/10342,to Zeneca Limited, published Mar. 4, 1999) in place of oxazolidinonecompound 1010, and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-phenylacetaldehyde 1032(which can be made by reduction of the corresponding carboxyl acid) inplace of 4-formylphenylboronic acid 1005.

For Examples 21-30, the Suzuki coupling reaction step, i.e. step 3 ofthe present invention, is more typically conducted in which the “Q” and“Z” substituents are reversed from the “Q” and “Z” substituents ofExamples 1-20.

Example 21 Synthesis of Compound 21

Compound 21 can be prepared using a reaction scheme analogous to thatfor compound 1, using the boronic ester oxazolidinone compound 1037 inplace of oxazolidinone 1010 and pyridyl bromo aldehyde 1038 in place ofaldehyde compound 1005. Compound 1037 can be made from compound 1010using a procedure described in PCT application No. WO 2005/012271, toRib-X Pharmaceuticals, Inc., published Feb. 10, 2005.

Synthesis of Boronic Ester 1037

A suspension of(5S)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide1010 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) inanhydrous 1,4-dioxane (130 mL) was treated with4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol,1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) atroom temperature. The resulting reaction mixture was degassed threetimes under a steady stream of argon before being treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)(Pd(dppf)₂Cl₂, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. Theresulting reaction mixture was degassed three times under a steadystream of argon before being warmed to reflux for 7 h. When HPLC/MSshowed the reaction was complete, the reaction mixture was cooled toroom temperature before being treated with water (100 mL) and ethylacetate (100 mL). The two layers were separated, and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with water (2×50 mL) and saturated aqueous NaCl (50mL), dried over MgSO₄, and concentrated in vacuo. The residual brown oilwas further dried in vacuo to afford the(5S)-N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide1037 (18.8 g, 94%) as brown solids. This product was directly used insubsequent reactions without further purification. C₁₈H₂₄BFN₂O₅, HPLC/MS(ESI) m/e 379 (M⁺+H).

Synthesis of Compound 1038

A solution of 2,5-Dibromo-pyridine (22.2 g, 93.7 mmol, 1.0 equiv.) intoluene (1.2 L) was treated with nBuLi (70.25 ml, 112.4 mmol, 1.2equiv.) dropwise at −78° C. The resulting solution was stirred at −78°C. for about 30 minutes, and DMF (11 ml, 141 mmol, 1.5 equiv.) wasadded. The reaction solution was warmed up gradually to RT and thenstirred overnight. When TLC and MS showed the reaction was complete, thereaction mixture was concentrated in vacuo, and the residue was directlypurified by column chromatography (SiO₂, 10-30% EtOAc/Hexanes gradientelution) to afford 5-Bromo-pyridine-2-carbaldehyde (1038, 5.45 g, 31%yield) as yellowish white solid. For 1038: C6H4BrNO, LCMS (EI) m/e 187(M⁺+H).

Example 22 Synthesis of Compound 22

Compound 22 can be prepared using a reaction scheme analogous to thatfor compound 1, using the boronic ester oxazolidinone compound 1039 inplace of oxazolidinone 1010 and pyridyl bromo aldehyde 1038 in place ofaldehyde compound 1005. Compound 1039 can be made from compound 1025using a procedure analogous to that for making compound 1037 fromcompound 1010.

Example 23 Synthesis of Compound 23

Compound 23 can be prepared using a reaction scheme analogous to thatfor compound 1, using the boronic ester oxazolidinone compound 1040 inplace of oxazolidinone 1010 and pyridyl bromo aldehyde 1038 in place ofaldehyde compound 1005. Compound 1040 can be made from compound 1026using a procedure analogous to that for making compound 1037 fromcompound 1010.

Example 24 Synthesis of Compound 24

Compound 24 can be prepared using a reaction scheme analogous to thatfor compound 1, using the boronic ester oxazolidinone compound 1041 inplace of oxazolidinone 1010 and pyridyl bromo aldehyde 1038 in place ofaldehyde compound 1005. Compound 1041 can be made from compound 1027using a procedure analogous to that for making compound 1037 fromcompound 1010.

Example 25 Synthesis of Compound 25

Compound 25 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-4-pentyne 1028 in place of propargyl amine1002, using the boronic ester oxazolidinone compound 1037 in place ofoxazolidinone 1010 and pyridyl bromo aldehyde 1038 in place of aldehydecompound 1005.

Example 26 Synthesis of Compound 26

Compound 26 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002, using the boronicester oxazolidinone compound 1037 in place of oxazolidinone 1010 andpyridyl bromo aldehyde 1038 in place of aldehyde compound 1005.

Example 27 Synthesis of Compound 27

Compound 27 can be prepared using a reaction scheme analogous to thatfor compound 1, using N-methyl-1-amino-2-propyne (also known asN-methyl-propargyl amine (commercially available from Aldrich) 1030 inplace of propargyl amine 1002, using the boronic ester oxazolidinonecompound 1037 in place of oxazolidinone 1010 and pyridyl bromo aldehyde1038 in place of aldehyde compound 1005.

Example 28 Synthesis of Compound 28

Compound 28 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-1-methyl-2-propyne 1031 in place ofpropargyl amine 1002, using the boronic ester oxazolidinone compound1037 in place of oxazolidinone 1010 and pyridyl bromo aldehyde 1042 inplace of aldehyde compound 1005.

Example 29 Synthesis of Compound 29

Compound 29 can be prepared using a reaction scheme analogous to thatfor compound 1, using the boronic ester oxazolidinone compound 1037 inplace of oxazolidinone 1010, and pyridyl bromo benzaldehyde 1042 inplace of aldehyde compound 1005.

Synthesis of compound 1042

Pyridyl bromobenzaldehyde 1042 can be prepared by reacting2,5-dibromopyridine with 1-amino-1-methyl-2-propyne 1031, followed byreduction with DIBAL.

Example 30 Synthesis of Compound 30

Compound 30 can be prepared using a reaction scheme analogous to thatfor compound 1, using 1-amino-3-butyne (commercially available from ABChemicals) 1029 in place of propargyl amine 1002, using the boronicester oxazolidinone compound 1037 in place of oxazolidinone 1010, andpyridyl bromo benzaldehyde 1042 in place of aldehyde compound 1005.

Reverse of Components for Suzuki Coupling Reactions

The forgoing compounds of Examples 1-30 can all be prepared in which the“Q” and “Z” substituents with respect to Step 3 can be reversed, suchthat the Suzuki Coupling components are reversed.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents, includingcertificates of correction, patent application documents, scientificarticles, governmental reports, websites, and other references referredto herein is incorporated by reference in its entirety for all purposes.

EQUIVALENTS

The invention can be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A process for preparing a compound (I) having the formula

comprising the steps of: (Step 1) combining a compound (II) having the formula:

with a compound (III) having the formula: x—N₃   Compound (III) in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV) having the formula:

(Step 2) combining a compound (IV) with a compound (V) having the formula:

in a solvent in the presence of a reducing agent to form a compound (VI) having the formula:

(Step 3) combining compound (VI) with a compound (VII) having the formula:

in a solvent in the presence of a base and a palladium catalyst to form a compound (VIII) having the formula:

(Step 4) heating a compound (VIII), in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form a compound (I); wherein: A is selected from: phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; B is selected from: phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; Het-CH₂—R³ is selected from:

Q is a borane having the formula —BY₂, wherein: Y, at each occurrence, independently is selected from: a) —OH, b) —OC₁₋₆ alkyl, c) —OC₂₋₆ alkenyl, d) —OC₂₋₆ alkynyl, e) —OC₁₋₁₄ saturated, unsaturated, or aromatic carbocycle, f) C₁₋₆ alkyl, g) C₂₋₆ alkenyl, h) C₂₋₆ alkynyl, and i) C₁₋₁₄ saturated, unsaturated, or aromatic carbocycle, wherein any of b)-i) optionally is substituted with one or more halogens; alternatively, two Y groups taken together comprise a chemical moiety selected from: a) —OC(R⁴)(R⁴)C(R⁴)(R⁴)O—, and b) —OC(R⁴)(R⁴)CH₂C(R⁴)(R⁴)O—; alternatively, Q is a BF₃ alkali metal salt, a BF₃ ammonium salt, a BF₃ tetralkyl ammonium salt, a BF₃ phosphate salt, or 9-borabicyclo[3.3.1]nonane; X is selected from: a) —CH₂-phenyl, b) —SO-phenyl, c) —SO₂-phenyl, d) —CH₂—O-phenyl, e) —CH₂—O—CH₂-phenyl, f) —CH₂—O—R²¹, g) —Si—(R²¹)₃, and h) —P(O)—(W)₂, wherein each W is independently C₁₋₆ alkyl or phenyl; each R²¹ is independently C₁₋₆ alkyl; each phenyl in a), b), c), d), e), or h) is optionally substituted with one or more R¹², wherein R¹² is selected from the group consisting of a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR²², g) —CN, h) —NO₂, i) —NR²²R²², j) —C(O)R²², k) —C(O)OR²², l) —OC(O)R²², m) —C(O)NR²²R²², n) —NR²²C(O)R²², o) —OC(O)NR²²R²², p) —NR²²C(O)OR²², q) —NR²²C(O)NR²²R²², r) —C(S)R²², s) —C(S)OR²², t) —OC(S)R²², u) —C(S)NR²²R²², v) —NR²²C(S)R²², w) —OC(S)NR²²R²², x) —NR²²C(S)OR²², y) —NR²²C(S)NR²²R²², z) —C(NR²²)R²², aa) —C(NR²²)OR²², bb) —OC(NR²²)R²², cc) —C(NR²²)NR²²R²², dd) —NR²²C(NR²²)R²², ee) —OC(NR²²)NR²²R²², ff) —NR²²C(NR²²)OR²², gg) —NR²²C(NR²²)NR²²R²², hh) —S(O)_(p)R²², ii) —SO₂NR²²R²² and jj) R²², wherein each R²² is independently, H or C₁₋₆ alkyl; Z is selected from: a) I, b) Br, c) Cl, d) R⁹OSO₃—, and e) N₂BF₄; R¹, at each occurrence, independently is selected from: a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR^(4R) ⁴, hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴; R², at each occurrence, independently is selected from: a) F, b) Cl, c) Br, d) I, e) —CF₃, f) —OR⁴, g) —CN, h) —NO₂, i) —NR⁴R⁴, j) —C(O)R⁴, k) —C(O)OR⁴, l) —OC(O)R⁴, m) —C(O)NR⁴R⁴, n) —NR⁴C(O)R⁴, o) —OC(O)NR⁴R⁴, p) —NR⁴C(O)OR⁴, q) —NR⁴C(O)NR⁴R⁴, r) —C(S)R⁴, s) —C(S)OR⁴, t) —OC(S)R⁴, u) —C(S)NR⁴R⁴, v) —NR⁴C(S)R⁴, w) —OC(S)NR⁴R⁴, x) —NR⁴C(S)OR⁴, y) —NR⁴C(S)NR⁴R⁴, z) —C(NR⁴)R⁴, aa) —C(NR⁴)OR⁴, bb) —OC(NR⁴)R⁴, cc) —C(NR⁴)NR⁴R⁴, dd) —NR⁴C(NR⁴)R⁴, ee) —OC(NR⁴)NR⁴R⁴, ff) —NR⁴C(NR⁴)OR⁴, gg) —NR⁴C(NR⁴)NR⁴R⁴, hh) —S(O)_(p)R⁴, ii) —SO₂NR⁴R⁴, and jj) R⁴; R³ is selected from: a) —OR⁴, b) —NR⁴R⁴, c) —C(O)R⁴, d) —C(O)OR⁴, e) —OC(O)R⁴, f) —C(O)NR⁴R⁴, g) —NR⁴C(O)R⁴, h) —OC(O)NR⁴R⁴, i) —NR⁴C(O)OR⁴, j) —NR⁴C (O)NR⁴R⁴, k) —C(S)R⁴, l) —C(S)OR⁴, m) —OC(S)R⁴, n) —C(S)NR⁴R⁴, o) —NR⁴C(S)R⁴, p) —OC(S)NR⁴R⁴, q) —NR⁴C(S)OR⁴, r) —NR⁴C(S)NR⁴R⁴, s) —C(NR⁴)R⁴, t) —C(NR⁴)OR⁴, u) —OC(NR⁴)R⁴, v) —C(NR⁴)NR⁴R⁴, w) —NR⁴C(NR⁴)R⁴, x) —OC(NR⁴)NR⁴R⁴, y) —NR⁴C(NR⁴)OR⁴, z) —NR⁴C(NR⁴)NR⁴R⁴, aa) —S(O)_(p)R⁴, bb) —SO₂NR⁴R⁴, and cc) R⁴; R⁴, at each occurrence, independently is selected from: a) H, b) —OR⁶, c) C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k) —C(O)—[C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle], l) —C(O)-[₃₋₁₄ membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur], m) —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of c)-q) optionally is substituted with one or more R⁵ groups; R⁵, at each occurrence, is independently selected from: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁶, h) ═NOR⁶, i) ═N—NR⁶R⁶, j) —CF₃, k) —OR⁶, l) —CN, m) —NO₂, n) —NR⁶R⁶, o) —C(O)R⁶, p) -C(0)OR6, q) —OC(O)R⁶, r) —C(O)NR⁶R⁶, s) —NR⁶C(O)R⁶, t) —OC(O)NR⁶R⁶, u) —NR⁶C(O)OR⁶, v) —NR⁶C(O)NR⁶R⁶, w) —C(S)R⁶, x) —C(S)OR⁶, y) —OC(S)R⁶, z) —C(S)NR⁶R⁶, aa) —NR⁶C(S)R⁶, bb) —OC(S)NR⁶R⁶, cc) —NR⁶C(S)OR⁶, dd) —NR⁶C(S)NR⁶R⁶, ee) —C(NR⁶)R⁶, ff) —C(NR⁶)OR⁶, gg) —OC(NR⁶)R⁶, hh) —C(NR⁶)NR⁶R⁶, ii) —NR⁶C(NR⁶)R⁶, jj) —OC(NR⁶)NR⁶R⁶, kk) —NR⁶C(NR⁶)OR⁶, ll) —NR⁶C(NR⁶)NR⁶R⁶, mm) —S(O)_(p)R⁶, nn) —SO₂NR⁶R⁶, oo) —N₃, pp) —Si(CH₃)₃, qq) —O—Si(CH₃₎ ₃, rr) —Si(C₂H₅)₂CH₃, ss) —O—Si(C₂H₅)₂CH₃, and tt) R⁶; R⁶, at each occurrence, independently is selected from: a) H, b) —OR⁸, c) C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of c)-q) optionally is substituted with one or more R⁷ groups; R⁷, at each occurrence, independently is selected from: a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR⁸, h) ═NOR⁸, i) ═N—NR⁸R⁸, j) —CF₃, k) —OR8, l) —CN, m) —NO₂, n) —NR⁸R⁸, o) —C(O)R⁸, p) —C(O)OR⁸, q) —OC(O)R⁸, r) —C(O)NR⁸R⁸, s) —NR⁸C(O)R⁸, t) —OC(O)NR⁸R⁸, u) —NR⁸C(O)OR⁸, v) —NR⁸C(O)NR⁸R⁸, w) —C(S)R⁸, x) —C(S)OR⁸, y) —OC(S)R⁸, z) —C(S)NR⁸R⁸, aa) —NR⁸C(S)R⁸, bb) —OC(S)NR⁸R⁸, cc) —NR⁸C(S)OR⁸, dd) —NR⁸C(S)NR⁸R⁸, ee) —C(NR⁸)R⁸, ff) —C(NR⁸)OR⁸, gg) —OC(NR⁸)R⁸, hh) —C(NR⁸)NR⁸R⁸, ii) —NR⁸C(NR⁸)R⁸, jj) —OC(NR⁸)NR⁸R⁸, kk) —NR⁸C(NR⁸)OR⁸, ll) —NR⁸C(NR⁸)NR⁸R⁸, mm) —S(O)_(p)R⁸, nn) —SO₂NR⁸R⁸, oo) C₁₋₆ alkyl, pp) C₂₋₆ alkenyl, qq) C₂₋₆ alkynyl, rr) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of oo)-ss) optionally is substituted with one or more moieties selected from R⁸, F, Cl, Br, I, —CF₃, —OR⁸, —SR⁸, —CN, —NO₂, —NR⁸R⁸, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —C(O)NR⁸R⁸, —NR⁸C(O)R⁸, —OC(O)NR⁸R⁸, —NR⁸C(O)OR⁸, —NR⁸C(O)NR⁸R⁸, —C(S)R⁸, —C(S)OR⁸, —OC(S)R⁸, —C(S)NR⁸R⁸, —NR⁸C(S)R⁸, —OC(S)NR⁸R⁸, —NR⁸C(S)OR⁸, —NR⁸C(S)NR⁸R⁸, —C(NR⁸)R⁸, —C(NR⁸)OR⁸, —OC(NR⁸)R⁸, —C(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)R⁸, —OC(NR⁸)NR⁸R⁸, —NR⁸C(NR⁸)OR⁸, —NR⁸C(NR⁸)NR⁸R⁸, —SO₂NR⁸R⁸, and —S(O)_(p)R⁸; R⁸, at each occurrence, independently is selected from: a) H, b) an amine protecting group, c) C₁₋₆ alkyl, d) C₂₋₆ alkenyl, e) C₂₋₆ alkynyl, f) C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C₁₋₆ alkyl, i) —C(O)—C₂₋₆ alkenyl, j) —C(O)—C₂₋₆ alkynyl, k) —C(O)—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C₁₋₆ alkyl, n) —C(O)O—C₂₋₆ alkenyl, o) —C(O)O—C₂₋₆ alkynyl, p) —C(O)O—C₃₋₁₄ saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of c)-q) optionally is substituted with one or more moieties selected from F, Cl, Br, I, —CF₃, —OH, —OC₁₋₆ alkyl, —SH, —SC₁₋₆ alkyl, —CN, —NO₂, —NH₂, —NHC₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, —C(O)C₁₋₆ alkyl, —C(O)OC₁₋₆ alkyl, —C(O)NH₂, —C(O)NHC₁₋₆ alkyl, —C(O)N(C₁₋₆ alkyl)₂, —NHC(O)C₁₋₆ alkyl, —SO₂NH₂—, —SO₂NHC₁₋₆ alkyl, —SO₂N(C₁₋₆ alkyl)₂, and —S(O)_(p)C₁₋₆ alkyl; R⁹ is selected from: a) C₁₋₆ alkyl, b) phenyl, and c) toluyl, wherein any of a)-c) optionally is substituted with one or more moieties selected from F, Cl, Br, and I; R¹⁰ is selected from H and C₁₋₈ alkyl; R¹¹ is selected from H and C₁₋₈ alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p, at each occurrence, independently is 0, 1, or 2; s is 1, 2, 3, 4, 5, or 6; and t is 0, 1, 2, 3, 4, 5, or 6, wherein —(CH₂)_(s)— and —(CH₂)_(t), other than when t is 0, are optionally substituted on any carbon atom thereof by one or more moieties selected from a) C₁₋₆ alkyl, b) C₁₋₆ alkenyl, c) phenyl, d) hydroxyl, e) C₁₋₆ alkoxy, f) F, g) Cl, h) Br, i) I, j) ═O, and k) benzyl.
 2. The process according to claim 1, having the formula: further comprising (Step 5) combining compound (I) with an acid to form a salt thereof.
 3. A process for preparing a compound (I) having the formula

comprising the step of (Step 4) heating a compound (VIII) having the formula:

in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form a compound (I), wherein: A, B, Het-CH₂—R³, X, Q, Z, R¹, R², R³ R¹⁰, R¹¹, m, n, p, s and t are as defined in claim
 1. 4. A process for preparing a compound (I) having the formula:

comprising the steps of: (Step 4) heating a compound (VIII) having the formula:

in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form a compound (I); and (Step 5) combining a compound (I) with an acid to form a salt thereof; wherein: A, B, Het-CH₂—R³, Q, Z, R¹, R², R³ R¹⁰, R¹¹, m, n, p, s and t are as defined in claim
 1. 5. The process according to claim 1, wherein A is selected from phenyl and pyridyl; B is selected from phenyl and pyridyl; m is 0, 1, or 2; and n is 0, 1, or
 2. 6. The process according to claim 1, wherein A is selected from phenyl and pyridyl; B is phenyl; m is 0; and n is 0, 1, or
 2. 7. The process according to claim 1, wherein R³ is selected from triazole, tetrazole, oxazole, and isoxazole.
 8. The process according to claim 1 wherein X is selected from a) para-methoxybenzyl, b) para-toluenesulfonyl, c) trimethylsilyl, and d) diphenylphosphoryl.
 9. The process according to claim 1 wherein X is para-methoxybenzyl.
 10. The process according to claim 1 wherein the solvent of (Step 1) is selected from toluene, dimethylformamide, dioxane, and tetrahydrofuran.
 11. The process according to claim 1 wherein (Step 1) is carried out at a temperature between about 60° C. and about 130° C.
 12. The process according to claim 1, wherein (Step 1) is carried out in the presence of a copper catalyst at a temperature of about 25° C.
 13. The process according to claim 1 wherein Het-CH₂—R³ is:


14. The process according to claim 1 wherein Het-CH₂—R³ is selected from:


15. The process according to claim 1 wherein the reducing agent of (Step 2) is a boron reducing agent or a combination of a palladium catalyst and hydrogen.
 16. The process according to claim 1 wherein said solvent of (Step 2) is selected from the group consisting a) methanol, b) ethanol, c) propanol, d) isopropanol, e) butanol, f) isobutanol, g) secondary butanol, h) tertiary butanol, i) dichloromethane, j) 1,1,-dichloroethan, k) tetrahydrofuran, and l) dimethylformamide and mixtures thereof.
 17. The process according to claim 1, wherein the base of (Step 3) is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal fluorides, trialkyl amines, and mixtures thereof.
 18. The process according to claim 17, wherein the ratio of equivalents of base of (Step 3) to equivalents of compound (VI) is about 3:1.
 19. The process according to claim 1, wherein the palladium catalyst of (Step 3) is a ligand coordinated palladium (0) catalyst.
 20. The process according to claim 19, wherein in (Step 3) the ratio of the equivalents of the coordinated palladium (0) catalyst to the equivalents of compound (VI) is about 1:20.
 21. The process according to claim 1, wherein the solvent of (Step 3) comprises an aqueous solvent.
 22. The process according to claim 1, wherein (Step 3) is carried out at a temperature between about 20° C. and about 100° C.
 23. The process according to claim 1 wherein the acid of (Step 4) is trifluoroacetic acid.
 24. The process according to claim 2 wherein the acid of (Step 5) is selected from acetic acid, adipic acid, ascorbic acid, citric acid, 2,5-dihydroxybenzoic acid, 2,3,4,5-tetrahydroxyhexane-1,6-dicarboxylic acid, glutamic acid, glycolic acid, benzenesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, gluconic acid, glutamic acid, hippuric acid, hydrochloric acid, gluconic acid, maleic acid, malic acid, malonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,2-disulfonic acid, oxalic acid, phosphoric acid, citric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and mixtures thereof.
 25. A process for preparing a compound (I) having the formula

comprising the steps of: (Step 1) combining a compound (II) having the formula:

with a compound (III) having the formula: X—N₃   Compound (III) in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV) having the formula:

(Step 2) combining a compound (IV) with a compound (V-a) having the formula

in a solvent in the presence of a reducing agent to form a compound (VI-a) having the formula:

(Step 3) combining compound (VI-a) with a compound (VII-a) having the formula:

in a solvent in the presence of a base and a palladium catalyst to form a compound (VIII) having the formula,

(Step 4) heating a compound (VIII), in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form a compound (I); wherein A, B, Het-CH₂—R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and t are as defined in claim
 1. 26. The process of claim 25, further comprising: (Step 5) combining compound (I) with an acid to form a salt thereof. 27.-28. (canceled)
 29. A process for preparing a compound (I-b) having the formula

comprising the steps of: (Step 1) combining a compound (II-b) having the formula:

with a compound (III) having the formula: X—N₃   Compound (III) in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV-b) having the formula:

(Step 2) combining a compound (IV-b) with a compound (V) having the formula:

in a solvent in the presence of a reducing agent to form compound (VI-b) having the formula

(Step 2-1) combining a compound (VI-b) with a protecting group reagent in a solvent in the presence of a base to form protected compound (VI-b-P) having the formula

(Step 3) combining a compound (VI-b-P) with a compound (VII) having the formula:

in a solvent in the presence of a base and a palladium catalyst to form compound (VIII-b-P) having the formula:

(Step 3-1) deprotecting a compound (VIII-b-P) in a solvent to form compound (VIII-b) or a salt thereof having the formula:

(Step 4) heating compound (VIII-b) in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (I-b); wherein A, B, Het-CH₂—R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and t are as defined in claim
 1. 30. The process of claim 29, further comprising (Step 5): combining compound (I-b) with an acid to form a salt thereof.
 31. The process according to claim 29 wherein the protecting group reagent of (Step 2-1) is selected such that the —N-Protecting Group of Compound (VI-a-P) is selected from a) N-benzyl, b) N-t-butyldimethylsilyl, c) N-t-butdyldiphenylsilyl, d) N-t-butyloxycarbonyl, e) N-p-methoxybenzyl, f) N-methoxymethyl, g) N-tosyl, h) N-trifluoroacetyl, i) N-trimethylsilyl, j) N-fluorenyl-methyloxycarbonyl, k) N-2-trimethylsilyl-ethyoxycarbonyl, l) N-1-methyl-1-(4-biphenylyl)ethoxycarbonyl, m) N-allyloxycarbonyl, and n) N-benzyloxycarbonyl.
 32. The process according to claim 29, wherein the base of (Step 2-1) is selected from potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium fluoride, triethylamine, diisopropylethylamine, and mixtures thereof.
 33. The process according to claim 29, wherein the acid of (Step 3-1) is selected from acetic acid, adipic acid, ascorbic acid, citric acid, 2,5-dihydroxybenzoic acid, 2,3,4,5-tetrahydroxyhexane-1,6-dicarboxylic acid, glutamic acid, glycolic acid, benzenesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, gluconic acid, glutamic acid, hippuric acid, hydrochloric acid, gluconic acid, maleic acid, malic acid, malonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,2-disulfonic acid, oxalic acid, phosphoric acid, citric acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and mixtures thereof.
 34. The process according to claim 29 wherein the solvent of (Step 3-1) is selected from a) methanol, b) ethanol, c) propanol, d) isopropanol, e) butanol, f) isobutanol, g) secondary butanol, h) tertiary butanol, i) benzene, j) toluene, k) tetrahydrofuran, l) dimethylformamide, m) 1,2-diethyl ether, n) dimethoxyethane, o) diisopropyl ether, p) methyltertiarybutyl ether, q) methoxymethyl ether, r) 2-methoxyethyl ether, s) 1,4-dioxane, t) 1,3-dioxolane, u) ethyl acetate, v) dichloromethane, w) 1,1-dichloroethane, and mixtures thereof.
 35. A process for preparing a compound (I-b) having the formula

comprising the steps of: (Step 1) combining a compound (II-b) having the formula:

with a compound (III) having the formula: X—N₃   Compound (III) in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV-b) having the formula:

(Step 2) combining a compound (IV-b) with a compound (V) having the formula:

in a solvent in the presence of a reducing agent to form compound (VI-b) having the formula

(Step 2-1) combining a compound (VI-a) with a protecting group reagent in a solvent in the presence of a base to form protected compound (VI-b-P) having the formula:

(Step 3) combining a compound (VI-b-P) with a compound (VII-a) having the formula:

in a solvent in the presence of a base and a palladium catalyst to form compound (VIII-b-P) having the formula:

(Step 3-1) deprotecting a compound (VIII-b-P) in a solvent in the presence of an acid to form compound (VIII-b) having the formula:

(Step 4) heating compound (VIII-b) in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (I-b); wherein A, B, Het-CH₂—R³, Q, Z, R¹, R², R³, R¹⁰, R¹¹, m, n, p, s, and t are as defined in claim
 1. 36. The process of claim 35, further comprising (Step 5) combining compound (I-b) with an acid to form a salt thereof.
 37. A process for preparing a compound (1)

comprising the steps of: (Step 1) combining a compound (1002):

with a compound (1001):

in toluene at about 100° C. to form a mixture of compounds (1003) and (1004):

(Step 2) combining said mixture of compounds (1003) and (1004) with a compound of formula (1005):

in a solvent selected from THF and DCE in the presence of a boron reducing agent to form a mixture of compounds (1006) and (1007):

(Step 2-1) combining a mixture of compounds of formulas (1006) and (1007) with di-tertbutyl carbonate in a solvent in the presence of a base to form a mixture of protected compounds (1008) and (1009):

(Step 3) combining a mixture of compounds of formulas (1008) and (1009) with a compound of formula (1010):

in a solvent in the presence of a base and a palladium catalyst to form a mixture of compounds of formulas (1011) and (1012):

(Step 3-1) deprotecting a mixture of compounds of formulas (1011) and (1012) in a solvent in the presence of an acid to form a mixture of compounds of formulas (1013) and (1014) or salts thereof:

(Step 4) heating a mixture of compounds of formula (1013) and (1014) or salts thereof, in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (1).
 38. A process for preparing a compound (1)

comprising the step of: (Step 4) heating a mixture of compounds of formula (1013) and (1014) or salts thereof:

in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (1).
 39. The process according to claim 37 further comprising the step (Step 5) of combining compound (1) with an acid to form a salt thereof.
 40. The process according to claim 29, wherein Compound I-b is compound (2):

comprising the steps of: (Step 1) combining a compound (1002):

with a compound (1001):

in toluene at about 100° C. to form a mixture of compounds (1003) and (1004):

(Step 2) combining said mixture of compounds (1003) and (1004) with a compound of formula (1005):

in a solvent selected from THF and DCE in the presence of a boron reducing agent to form a mixture of compounds (1006) and (1007):

(Step 2-1) combining a mixture of compounds of formulas (1006) and (1007) with di-tertbutyl carbonate in a solvent in the presence of a base to form a mixture of protected compounds (1008) and (1009):

(Step 3) combining a mixture of compounds of formulas (1008) and (1009) with a compound of formula (1025):

in a solvent in the presence of a base and a palladium catalyst to form a mixture of compounds of formulas (2-i-P) and (2-ii-P):

(Step 3-1) deprotecting a mixture of compounds of formulas (2-i-P) and (2-ii-P) in a solvent in the presence of an acid to form a mixture of compounds of formulas (2-i) and (2-ii) or salts thereof:

(Step 4) heating a mixture of compounds of formula (2-i) and (2-ii) or salts thereof, in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (2).
 41. (canceled)
 42. The process according to claim 40 further comprising the step of (Step 5) combining compound (2) with an acid to form a salt thereof.
 43. The process according to claim 29, wherein Compound I-b is compound (3)

comprising the steps of: (Step 1) combining a compound (1002)

with a compound (1001)

in toluene at about 100° C. to form a mixture of compounds (1003) and (1004)

(Step 2) combining said mixture of compounds (1003) and (1004) with a compound of formula (1005):

in a solvent selected from THF and DCE in the presence of a boron reducing agent to form a mixture of compounds (1006) and (1007):

(Step 2-1) combining a mixture of compounds of formulas (1006) and (1007) with di-tertbutyl carbonate in a solvent in the presence of a base to form a mixture of protected compounds (1008) and (1009):

(Step 3) combining a mixture of compounds of formulas (1008)and (1009) with a compound of formula (1026):

in a solvent in the presence of a base and a palladium catalyst to form a mixture of compounds of formulas (3-i-P) and (3-ii-P),

(Step 3-1) deprotecting a mixture of compounds of formulas (3-i-P) and (3-ii-P) in a solvent in the presence of an acid to form a mixture of compounds of formulas (3-i) and (3-ii) or salts thereof:

(Step 4) heating a mixture of compounds of formula (3-i) and (3-ii) or salts thereof, in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (3).
 44. (canceled)
 45. The process according to claim 43 further comprising the step of (Step 5) combining compound (3) with an acid to form a salt thereof.
 46. The process according to claim 29, wherein Compound I-b is compound (4)

comprising the steps of: (Step 1) combining a compound (1002)

with a compound (1001):

in toluene at about 100° C. to form a mixture of compounds (1003) and (1004):

(Step 2) combining said mixture of compounds (1003) and (1004) with a compound of formula (1005):

in a solvent selected from THF and DCE in the presence of a boron reducing agent to form a mixture of compounds (1006) and (1007):

(Step 2-1) combining a mixture of compounds of formulas (1006) and (1007) with di-tertbutyl carbonate in a solvent in the presence of a base to form a mixture of protected compounds (1008) and (1009):

(Step 3) combining a mixture of compounds of formulas (1008)and (1009) with a compound of formula (1027):

in a solvent in the presence of a base and a palladium catalyst to form a mixture of compounds of formulas (4-i-P) and (4-ii-P):

(Step 3-1) deprotecting a mixture of compounds of formulas (4-i-P) and (4-ii-P) in a solvent in the presence of an acid to form a mixture of compounds of formulas (4-i) and (4-ii) or salts thereof:

(Step 4) heating a mixture of compounds of formula (4-i) and (4-ii) or salts thereof, in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (4).
 47. (canceled)
 48. The process according to claim 46 further comprising the step of (Step 5) combining compound (4) with an acid to form a salt thereof.
 49. The process according to claim 29, wherein Compound I-b is compound (2)

comprising the steps of: (Step 1) combining a compound (1002)

with a compound (1001):

in toluene at about 100° C. to form a mixture of compounds (1003) and (1004):

(Step 2) combining said mixture of compounds (1003) and (1004) with a compound of formula (1005):

in a solvent selected from THF and DCE in the presence of a boron reducing agent to form a mixture of compounds (1006) and (1007):

(Step 2-1) combining a mixture of compounds of formulas (1006) and (1007) with di-tertbutyl carbonate in a solvent in the presence of a base to form a mixture of protected compounds (1008) and (1009):

(Step 3) combining a mixture of compounds of formulas (1008)and (1009) with a compound of formula (1024-i) or (1024-ii):

in a solvent in the presence of a base and a palladium catalyst to form a mixture of compounds of formulas (2-ia-P) or (2-ib-P) and (2-iia-P) or (2-iib-P):

(Step 3-1) deprotecting a mixture of compounds of formulas (2-ia-P) or (2-ib-P) and (2-iia-P) or (2-iib-P) in a solvent in the presence of an acid to form a mixture of compounds of formulas (2-ia) or (2-ib) and (2-iia) or (2-iib) or salts thereof:

(Step 4) heating a mixture of compounds of formula (2-ia) or (2-ib) and (2-iia) or (2-iib) or salts thereof, in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form compound (2), wherein each R²⁰ is independently C₁-C₆ alkyl or —O—(C₁-C₆ alkyl).
 50. (canceled)
 51. The process according to claim 49 further comprising the step of (Step 5) combining compound (2) with an acid to form a salt thereof.
 52. A compound corresponding to the structure

or a pharmaceutically acceptable salt thereof, wherein each R²⁰ is independently C₁-C₆ alkyl or —O—(C₁-C₆ alkyl).
 53. The compound according to claim 52 wherein each R²⁰ is methyl.
 54. A process for preparing a compound having the formula:

formula: wherein the process includes the steps of: (Step 1) combining a compound (II) having the formula:

with a compound (III) having the formula: X—N₃   Compound (III) in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV), wherein X, R¹¹, and s, are as defined in claim
 1. 55. A hydrochloride salt of a compound having the formula: 